Multiplicity of mechanisms of serotonin receptor signal transduction

Associate editor: B.L. Roth

Multiplicity of mechanisms of serotonin receptor signal transduction

John R. Raymonda,b,*, Yurii V. Mukhinb, Andrew Gelascoa,b, Justin Turnerb,Georgiann Collinswortha,b, Thomas W. Gettysc, Jasjit S. Grewalb, Maria N. Garnovskayaa,b

aThe Research Service of the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401, USAbDepartments of Medicine (Nephrology Division), Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA

cDepartments of Medicine (Gastroenterology Division) and Biochemistry and Molecular Biology,

Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA

Abstract

The serotonin (5-hydroxytryptamine, 5-HT) receptors have been divided into 7 subfamilies by convention, 6 of which include 13 different

genes for G-protein-coupled receptors. Those subfamilies have been characterized by overlapping pharmacological properties, amino acid

sequences, gene organization, and second messenger coupling pathways. Post-genomic modifications, such as alternative mRNA splicing or

mRNA editing, creates at least 20 more G-protein-coupled 5-HT receptors, such that there are at least 30 distinct 5-HT receptors that signal

through G-proteins. This review will focus on what is known about the signaling linkages of the G-protein-linked 5-HT receptors, and will

highlight some fascinating new insights into 5-HT receptor signaling. D 2001 Elsevier Science Inc. All rights reserved.

Keywords: Signal transduction; Adenylyl cyclase; Phospholipase; Kinase; Channel

Abbreviations: AA, arachidonic acid; AC, adenylyl cyclase; CaM, calmodulin; cAMP, cyclic AMP; cGMP, cyclic GMP; CHO, Chinese hamster ovary;

cNOS, constitutive nitric oxide synthase; iNOS, inducible nitric oxide synthase; DAG, diacylglycerol; ERK, extracellular signal-regulated kinase;

GABA, g-aminobutyric acid; GIRK, G-protein-gated inwardly rectifying K+; GPCR, G-protein-coupled receptor; HEK, human embryonic kidney; 5-HT,

5-hydroxytryptamine, serotonin; IP3, inositol trisphosphate; IRK, inward rectifier K+; Jak, Janus kinase; LSD, lysergic acid diethylamide; MAP, mitogen-

activated protein; MEK, mitogen and extracellular signal-regulated kinase; MUPP1, multi-PS-95 discs-large ZO-1 interaction motif-domain protein;

NMDA, N-methyl-D-aspartic acid; NO, nitric oxide; NOS, nitric oxide synthase; 8-OH-DPAT, (±)-8-hydroxy-2-(di-N-propylamino)tetralin; PC-PLC,

phosphatidylcholine-specific phospholipase C; PDGF, platelet-derived growth factor; PDZ, PS-95 discs-large ZO-1, which is a type of protein-protein

interaction motif; PI, phosphatidylinositol; PI-PLC, phosphatidylinositol-specific phospholipase C; PKA, protein kinase A; PKC, protein kinase C; PL,

phospholipase; RGS, regulators of G-protein signaling; SRL, serotonin receptor-like; STAT, signal transducers and activators of transcription.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

2. The 5-hydroxytryptamine1 receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

2.1. The 5-hydroxytryptamine1A receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

2.1.1. The 5-hydroxytryptamine1A receptor both inhibits and activates adenylyl cyclase 184

2.1.2. The 5-hydroxytryptamine1A receptor activates and inhibits phosphatidylinositol-

specific phospholipase C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

2.1.3. The 5-hydroxytryptamine1A receptor activates other phospholipases . . . . . . . 185

2.1.4. The 5-hydroxytryptamine1A receptor activates protein kinase C . . . . . . . . . 185

2.1.5. The 5-hydroxytryptamine1A receptor activates the extracellular signal-regulated

mitogen-activated protein kinase . . . . . . . . . . . . . . . . . . . . . . . . . 185

2.1.6. The 5-hydroxytryptamine1A receptor stimulates phosphatidylinositol-30 kinase. . 186

0163-7258/01/$ – see front matter D 2001 Elsevier Science Inc. All rights reserved.

PII: S0163 -7258 (01 )00169 -3

* Corresponding author: Room 829 CSB, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA. Tel.: 843-792-4122;

fax: 843-792-8399.

E-mail address: [email protected] (J.R. Raymond).

Pharmacology & Therapeutics 92 (2001) 179–212

2.1.7. The 5-hydroxytryptamine1A receptor causes production of reactive oxygen and

nitrogen species. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186

2.1.8. The 5-hydroxytryptamine1A receptor regulates K+ channels . . . . . . . . . . . 186

2.1.9. The 5-hydroxytryptamine1A receptor inhibits neuronal Ca2+ conductances . . . . 187

2.1.10. The 5-hydroxytryptamine1A receptor regulates other ion channels . . . . . . . . 187

2.1.11. The 5-hydroxytryptamine1A receptor regulates miscellaneous transport processes 187

2.1.12. The 5-hydroxytryptamine1A receptor regulates proliferation and related pathways 187

2.1.13. What is the basis for the multiplicity of 5-hydroxytryptamine1Areceptor signaling? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

2.2. The 5-hydroxytryptamine1B receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

2.2.1. The 5-hydroxytryptamine1B receptor regulates adenylyl cyclase . . . . . . . . . 188

2.2.2. The 5-hydroxytryptamine1B receptor activates phospholipases . . . . . . . . . . 189

2.2.3. The 5-hydroxytryptamine1B receptor regulates the extracellular signal-regulated

kinase, phosphatidylinositol-30 kinase, p70 S6 kinase, and Akt kinase . . . . . . 189

2.2.4. The 5-hydroxytryptamine1B receptor stimulates endothelial nitric oxide production 189

2.2.5. Other signals of the 5-hydroxytryptamine1B receptor . . . . . . . . . . . . . . . 189

2.3. The 5-hydroxytryptamine1D receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

2.3.1. The 5-hydroxytryptamine1D receptor inhibits adenylyl cyclase . . . . . . . . . . 190

2.3.2. The 5-hydroxytryptamine1D receptor regulates ion channels . . . . . . . . . . . 190

2.3.3. The 5-hydroxytryptamine1D receptor is mitogenic . . . . . . . . . . . . . . . . 190

2.3.4. The 5-hydroxytryptamine1D receptor inhibits 5-hydroxytryptamine release . . . 190

2.4. The 5-hydroxytryptamine1E receptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

2.5. The 5-hydroxytryptamine1F receptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . 190


3.1. The 5-hydroxytryptamine2A receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

3.1.1. The 5-hydroxytryptamine2A receptor activates phospholipase C . . . . . . . . . 191

3.1.2. The 5-hydroxytryptamine2A receptor activates other phospholipases . . . . . . . 191

3.1.3. The 5-hydroxytryptamine2A receptor can regulate cyclic amp accumulation in

certain cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

3.1.4. 5-hydroxytryptamine2A receptor activates the extracellular signal-regulated

mitogen-activated protein kinase . . . . . . . . . . . . . . . . . . . . . . . . . 192

3.1.5. The 5-hydroxytryptamine2A receptor activates the Janus kinase/signal transducers

and activators of transcription pathway . . . . . . . . . . . . . . . . . . . . . . 192

3.1.6. The 5-hydroxytryptamine2A receptor regulates apoptosis . . . . . . . . . . . . . 192

3.1.7. The 5-hydroxytryptamine2A receptor regulates channels . . . . . . . . . . . . . 192

3.1.8. The 5-hydroxytryptamine2A receptor causes production of reactive oxygen and


3.1.9. The 5-hydroxytryptamine2A receptor regulates calmodulin . . . . . . . . . . . . 192

3.1.10. The 5-hydroxytryptamine2A receptor regulates transport processes . . . . . . . 193

3.1.11. A unique signaling role for internalization of the 5-hydroxytryptamine2A receptor 193

3.2. The 5-hydroxytryptamine2B receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

3.2.1. The 5-hydroxytryptamine2B receptor activates phospholipase C . . . . . . . . . 193

3.2.2. The 5-hydroxytryptamine2B receptor can stimulate cyclic amp accumulation . . 193

3.2.3. The 5-hydroxytryptamine2B receptor regulates morphogenesis and mitogenesis . 193

3.2.4. The 5-hydroxytryptamine2B receptor activates the extracellular signal-regulated

kinase and cell cycle components . . . . . . . . . . . . . . . . . . . . . . . . 194

3.2.5. The 5-hydroxytryptamine2B receptor causes production of reactive


3.2.6. The 5-hydroxytryptamine2B receptor regulates channels . . . . . . . . . . . . . 194

3.2.7. The 5-hydroxytryptamine2B receptor regulates transport processes . . . . . . . . 194

3.3. The 5-hydroxytryptamine2C receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

3.3.1. The 5-hydroxytryptamine2C receptor activates phospholipase C . . . . . . . . . 195

3.3.2. The 5-hydroxytryptamine2C receptor can modulate cyclic amp accumulation . . 195

3.3.3. The 5-hydroxytryptamine2C receptor regulates channels . . . . . . . . . . . . . 195

3.3.4. The 5-hydroxytryptamine2C receptors regulate mitogenesis . . . . . . . . . . . 196

3.3.5. The 5-hydroxytryptamine2C receptor can regulate nitric oxide levels. . . . . . . 196

3.3.6. The 5-hydroxytryptamine2C receptor regulates transport processes . . . . . . . . 196

3.3.7. Possible signaling through PS-95 discs-large ZO-1 interaction motifs by

the 5-hydroxytryptamine2C receptor . . . . . . . . . . . . . . . . . . . . . . . 196

3.3.8. Multiple novel functional 5-hydroxytryptamine2C receptors are created by

mrna editing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

J.R. Raymond et al. / Pharmacology & Therapeutics 92 (2001) 179–212180

4. The 5-hydroxytryptamine4 receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

4.1. The 5-hydroxytryptamine4 receptor activates adenylyl cyclase . . . . . . . . . . . . . . 197

4.2. The 5-hydroxytryptamine4 receptor activates protein kinase A . . . . . . . . . . . . . . 197

4.3. The 5-hydroxytryptamine4 receptor regulates channels . . . . . . . . . . . . . . . . . . 197

4.4. The 5-hydroxytryptamine4 receptor regulates transport . . . . . . . . . . . . . . . . . . 198

4.5. Functional differences among the 5-hydroxytryptamine4 receptor splice variants . . . . . 198


5.1. Functional coupling of the 5-hydroxytryptamine5 receptors to signaling pathways . . . . 198



6.2. The 5-hydroxytryptamine6 receptor splice variants . . . . . . . . . . . . . . . . . . . . 199


7.1. The 5-hydroxytryptamine7 receptor splice variants . . . . . . . . . . . . . . . . . . . . 199


7.3. The 5-hydroxytryptamine7 receptor activates the extracellular signal-regulated kinase . . 200

7.4. The 5-hydroxytryptamine7 receptor stimulates vasorelaxation . . . . . . . . . . . . . . . 200

7.5. The 5-hydroxytryptamine7 receptor modulates slow afterhyperpolarization . . . . . . . . 200

8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

1. Introduction

Serotonin (5-HT, 5-hydroxytryptamine) was discovered

in 1948 by Rapport et al. as a potent vasotonic factor. For

many years, the physiological effects of 5-HT, including its

effects on the CNS, were attributed to only two major

subtypes of 5-HT receptors (Gaddum & Picarelli, 1957).

Because of the development of sophisticated pharmaco-

logical tools in the 1980s, it became clear that there must

be more than two subtypes of 5-HT receptors. Molecular

cloning studies over the last 14 years have confirmed the

existence of at least 14 subtypes of 5-HT receptors, each

encoded by distinct genes. Splice variants of many of the

subtypes have been identified subsequently, resulting in

the discovery of at least 30 distinct protein products

that recognize 5-HT as their physiological ligand. Most

of the receptor genes (13) belong to a large family of

receptors that encode proteins that transduce signals

through guanine nucleotide binding and regulatory pro-

teins (G-proteins).

The 5-HT receptors have been divided into 7 subfamilies

by convention. Those subfamilies have been characterized

by overlapping pharmacological properties, amino acid

sequences, gene organization, and second messenger cou-

pling pathways (Hoyer et al., 1994). The 5-HT1, 5-HT2,

5-HT4, 5-ht5, 5-HT6, and 5-HT7 receptors couple to G-pro-

teins, whereas the 5-HT3 receptors are 5-HT-gated ion

channels. The basic architecture of the G-protein-coupled

5-HT receptors is similar to that proposed for nearly all of

the G-protein-coupled receptors (GPCRs). These receptors

are integral membrane proteins with 7 putative hydrophobic

transmembrane domains connected by 3 intracellular loops

(termed i1–i3) and 3 extracellular loops (termed e1–e3).

The amino terminus is oriented toward the extracellular

space, whereas the carboxyl terminus is oriented toward the

cytoplasm. The core proteins also possess conserved or

common sites for post-translational modifications. The

extracellular domains are typically glycosylated, and pos-

sess cysteine residues that may participate in disulfide

bonds that provide structural constraints on the conforma-

tion of the receptors. The intracellular domains possess sites

for interacting with G-proteins and other regulatory pro-

teins, and sites for phosphorylation by diverse serine-

threonine kinases. Some of the 5-HT receptors contain

PS-95 discs-large ZO-1 interaction motif (PDZ) domains

within their intracellular domains. Most of the 5-HT recep-

tors also possess cysteine residues within their carboxyl

termini that may be palmitoylated, thus creating potential

membrane anchors that can form a putative fourth intra-

cellular loop.

The purpose of this review is to summarize what is

known about the second messenger and effector linkages of

5-HT receptors, as revealed in native tissues and cells and

in heterologous expression systems. This is a timely and

important topic that already has been the subject of many

excellent reviews (for example, Hoyer et al., 1994; Boess &

Martin, 1994; Zifa & Fillion, 1992; Roth et al., 1998).

Recent studies have revealed a rich diversity of coupling

mechanisms for each 5-HT receptor subtype. The multipli-

city of coupling pathways for each of the receptors suggests

that each individual 5-HT receptor subtype can regulate a

broad array of potential signals that could be affected by

variables such as cell type, receptor number, numbers and

types of G-proteins expressed in the target cells, and the

specific agonist through which the receptor is activated.

This review will focus only upon the signaling linkages of

the cloned G-protein-coupled 5-HT receptors. We will not

discuss other 5-HT receptors, such as putative peripheral

‘‘5-HT1P’’ receptors (Pan et al., 1997), which have been

reviewed elsewhere (Gershon, 1999). The discussion will

J.R. Raymond et al. / Pharmacology & Therapeutics 92 (2001) 179–212 181

be organized so that each major receptor subfamily will be

discussed individually.

2. The 5-hydroxytryptamine1 receptors

There are 5 members of the 5-HT1 receptor family,

termed 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F. A

receptor formerly termed the 5-HT1C receptor is no longer

felt to be a member of the 5-HT1 receptor family, having

been reclassified as the 5-HT2C receptor (Hoyer et al.,

1994), based on similarities to other 5-HT2 receptors in

structure and second messenger systems. The 5-HT1 recep-

tors couple primarily through Gi/o-proteins to the inhibition

of adenylyl cyclase (AC) (see Fig. 1) and to a multitude of

other signaling pathways and effectors. These will be

reviewed in Sections 2.1–2.5.

2.1. The 5-hydroxytryptamine1A receptor

The 5-HT1A receptor is the best characterized of the

5-HT1 receptors (Pedigo et al., 1981; Middlemiss &

Fozard, 1983), in large part due to the wide availability

of many specific pharmacological tools and because its

cDNA and gene were cloned (Kobilka et al., 1987) and

identified (Fargin et al., 1988) over a decade ago. Like all

5-HT1 receptors, the 5-HT1A receptor is characterized

pharmacologically by its high affinity for 5-HT. It has a

uniquely high affinity for second generation, arylpipera-

zine anxiolytic agents, such as buspirone, gepirone, and

ipsapirone. The 5-HT1A receptor also has a high affinity

for ( ± )-8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-

DPAT), which previously was thought to be unique.

However, it is now known that the 5-HT7 receptor shares

a relatively high affinity for 8-OH-DPAT with the 5-HT1A

receptor. The 5-HT1A receptor plays potential roles in

neuro-endocrine function and thermoregulation (Goodwin

et al., 1985, 1987; Hjorth, 1985; Gilbert et al., 1988a;

Gartside et al., 1990; Seletti et al., 1995; Balcells-Olivero

et al., 1998), vasoreactive headaches (Leone et al., 1998),

sexual behavior (Ahlenius & Larsson, 1989; Schnur et al.,

1989; Maswood et al., 1998), food intake (Dourish et al.,

1985; Gilbert & Dourish, 1987; Hutson et al., 1988;

Gilbert et al., 1988b; Yamada et al., 1998), tooth-germ

morphogenesis (Moiseiwitsch et al., 1998), memory (Eda-

gawa et al., 1998), immune function (Iken et al., 1995),

aggression (Miczek et al., 1998), depression (Blier et al.,

1997; Shiah et al., 1998), and anxiety (Parks et al., 1998;

Ramboz et al., 1998), as have been demonstrated in

various physiological, clinical, behavioral, and pharmaco-

logical studies.

The 5-HT1A receptor was one of the first GPCRs for

which the cDNA and gene were cloned (Kobilka et al.,

1987; Fargin et al., 1988; Albert et al., 1990; Fujiwara et al.,

1990; Stam et al., 1992; Chanda et al., 1993). The human

receptor gene is localized on chromosome 5q11.2-q13

(Kobilka et al., 1987), and encodes a predicted protein with

422 amino acids. The gene is intronless, and its mRNA and

protein are expressed mainly in the brain, spleen, neonatal

kidney, and gut (Kobilka et al. 1987; Fargin et al. 1988;

Kirchgessner et al., 1993; Raymond et al., 1993a) (see

Table 1). The coding block of the genes for the rat and

human 5-HT1A receptor are 88% homologous with each

other at the nucleic acid level (Kobilka et al., 1987; Fargin

et al., 1988; Albert et al., 1990; Fujiwara et al., 1990; Stam

et al., 1992). Those sequences share substantially less

homology with other G-protein-coupled 5-HT receptors,

such as the 5-HT2A (19%), 5-HT2C (18%), and 5-HT1D

(43%) receptors (Fujiwara et al., 1990). The primordial

significance of the 5-HT1A receptor is underscored by the

molecular cloning of putative homologues in non-mam-

malian species, such as Xenopus laevis (Marracci et al.,

1997) and Fugu rubripes (Yamaguchi & Brenner, 1997).

The 5-HT1A receptor arguably couples to the broadest

panel of second messengers of any of the 5-HT receptors

(see Table 2). The 5-HT1A receptor has been reported to

activate or inhibit various enzymes, channels, and kinases,

and to stimulate or inhibit production of diverse soluble

second messengers. This receptor has been reported to

Fig. 1. Prototypical signaling enzyme linkages of the G-protein-coupled

5-HT receptors. 5-HT1 receptors typically inhibit AC through pertussis toxin-

sensitive G-proteins of the Gi family, whereas 5-HT4, 5-HT6, and 5-HT7

receptors typically stimulate AC through Gs family G-proteins. Activation

of AC results in increased production of cAMP, leading to activation of PKA.

5-HT2 receptors activate PLC-b through Gq/11 family G-proteins, resulting in

accumulation of phosphatidylinositol 4,5-bisphosphate (PIP2) to IP3 and

DAG. Generation of IP3 results in elevation of intracellular Ca2 + levels,

whereas DAG activates the Ca2 + and phospholipid-dependent protein kinase

(PKC). 5-HT2 receptors also typically activate PLA2 through G-proteins to

increase the accumulation of AA.


inhibit and activate AC and phospholipase (PL)C, and to

stimulate nitric oxide synthase (NOS) and an NAD(P)H

oxidase-like enzyme. It can activate K + channels and high-

conductance anion channels, inhibit Ca2 + conductances,

and regulate a number of channels and transporters. The

5-HT1A receptor can activate protein kinase C (PKC), Src

kinase, and mitogen-activated protein (MAP) kinases. The

5-HT1A receptor can inhibit or stimulate Ca2 + mobiliza-

Table 2

Signaling characteristics of human 5-HT receptors

Receptor Common signaling linkages Other signaling linkages G-protein coupling

5-HT1A Inhibits AC Activates PLC Gia3 > Gia2 � Gia1 � Goa > Gza

Activates K + channels Activates NOS

Stimulates ERK Activates NAD(P)H oxidase

Inhibits Ca2 + Activates NHE-1

conductances

5-HT1B Inhibits AC Activates PLC Gia3 > Gia1 � Gia2 � Goa

Stimulates ERK Activates NOS

Activates AC2

Activates K + channels

5-HT1D Inhibits AC Inhibits Ca2 + conductances Gia & Goa

Activates K + channels

5-HT1E Inhibits AC Gia & Goa

5-HT1F Inhibits AC Activates PLC Gia & Goa

5-HT2A Activates PLC Activates NHE-1 Gqa & G11a � Gia

Activates PKC Activates AC

Stimulates ERK Inhibits AC

Activates PLA2 Activates Jak2/STAT3

Activates Ca2 + channels

5-HT2B Activates PLC Activates cell cycle Gqa & G11a

Activates ERK Activates iNOS

Activates PLA2 Activates cNOS

5-HT2C Activates PLC Activates Na + /Ca2 + exchanger Gqa & G11a

Activates PKC PDZ motif signals?

Activates PLA2

5-HT4 Activates AC Regulates various channels Gsa

Activates PKA

5-ht5a Unknown Unknown Unidentified

5-ht5B Unknown Unknown Unidentified

5-HT6 Activates AC Gsa

Activates PKA

5-HT7 Activates AC Activates ERK Gsa

Activates PKA

This table is not all-encompassing. See text for more details and for primary literature citations.

Table 1

Characteristics of human 5-HT receptor genes

Human receptor Archaic names

Number of

amino acids

Chromosomal

location Introns

Functional

splice variants

mRNA editing

variants

5-HT1A 422 5q11.2-q13 0 0 0

5-HT1B 5-HT1Db 390 6q13 0 0 0

5-HT1D 5-HT1Da 377 1p34.3 0 0 0

5-HT1E 365 6q14-q15 0 0 0

5-HT1F 5-HT1Eb 366 3q11 0 0 0

5-HT2A 5-HT2;

5-HT D

471 13q14-q21 2 0 0

5-HT2B SRL;

5-HT2F

481 2q36.3-q37.1 2 0 0

5-HT2C 5-HT1C 460 Xq24 3 ?1 � 14

5-HT4 388 5q31-q33 � 5 � 5 0

5-ht5a 357 7q36 1 0 0

5-ht5B ? 2q11-q13 1 0 0

5-HT6 440 1p35-p36 2 ?1 0

5-HT7 445 10q21-q24 2 � 3 0

1 Nonfunctional variants have been described. See text for primary literature citations.


tion, activate or inhibit phosphatidyl inositol hydrolysis,

and stimulate production of reactive oxygen species (both

H2O2 and superoxide) and arachidonic acid (AA). In

nearly every case, the signals have been shown to be

almost completely sensitive to pertussis toxin, implicating

Gi/o-proteins in the signals initiated by the 5-HT1A receptor.

2.1.1. The 5-hydroxytryptamine1A receptor both inhibits and

activates adenylyl cyclase

The primary coupling of this receptor (and all 5-HT1

receptors) is to the inhibition of AC (De Vivo & Maayani,

1986; Weiss et al., 1986). In some systems, this is man-

ifested by an ability to suppress basal cyclic AMP (cAMP)

levels, whereas in others, it is primarily manifested by an

ability to inhibit forskolin-stimulated AC activity. The

number of cell types and lines in which the 5-HT1A

receptor inhibits AC is quite extensive. A partial list

includes hippocampal and cortical neurons (De Vivo &

Maayani, 1986; Weiss et al., 1986), cultured neuronal cells

(the NCB-20, F11, P-11, and HN2 lines) (Hensler et al.,

1996; Singh et al., 1996), Chinese hamster ovary (CHO)

fibroblasts (Raymond, 1991), HeLa cells (Fargin et al.,

1991), human embryonic kidney (HEK) 293 cells (Albert

et al., 1999; Kellett et al., 1999), NIH 3T3 fibroblasts

(Varrault & Bockaert, 1992; Varrault et al., 1992b), COS-7

cells (Fargin et al., 1989), GH4C1 pituitary cells and Ltk–

fibroblasts (Liu & Albert, 1991), LLC-PK1 (Langlois et al.,

1996), ventral prostate cells (Carmena et al., 1998), and even

insect (army worm) Sf9 cells (Mulheron et al., 1994). The

inhibition of AC by the 5-HT1A receptor is universally

pertussis toxin-sensitive, suggesting that this effect requires

Gi/o-proteins. Numerous studies in diverse expression sys-

tems (Escherichia coli, Spodoptera frugiperda, and mam-

malian cells) have shown remarkable consistency in the

ability of the 5-HT1A receptor to bind to G-proteins of this

class, with a consensus rank order of Gia3 > Gia2 � Gia1 �Goa > Gza (Bertin et al., 1992; Raymond et al., 1993b;

Mulheron et al., 1994; Butkerait et al., 1995; Barr et al.,

1997; Clawges et al., 1997; Garnovskaya et al., 1997). We

would like to point out that the consensus rank order of

G-protein coupling has been determined using only two

agonists (5-HT and 8-OH-DPAT). This is potentially

important in that we have previously shown using cells

transfected with the human 5-HT1A receptor, that the

relative efficacies (compared with 5-HT) of a small panel

of compounds to activate G-protein a-subunits is clearly

different, depending upon whether Gia3 or Gia2 was studied

(Gettys et al., 1994). Thus, the coupling of the 5-HT1A

receptor to various G-proteins may be influenced by the

agonist to which the receptor is exposed.

Several studies strongly support a role for either Gia3 or

Gia2 in mediating the inhibition of AC activity by the 5-HT1A

receptor in diverse mammalian cells (Fargin et al., 1991;

Raymond et al., 1993b; Liu et al., 1994; Langlois et al., 1996),

although Gia1 or Goa may play limited roles in some systems

(Raymond et al., 1993b; Mulheron et al., 1994).

Surprisingly, the 5-HT1A receptor does not universally

inhibit AC in all cell types. Despite being expressed in high

density in dorsal raphe neurons, 5-HT1A receptors have not

been shown to inhibit AC in the rat dorsal raphe (Clarke et al.,

1996). Moreover, there is no evidence for functional cou-

pling to the inhibition of AC in cultured astrocytes, although

multiple mRNAs for 5-HT1 receptors (including the 5-HT1A

receptor) are expressed there (Hirst et al., 1998). In contrast

to the findings of Clarke et al. (1996) in rat dorsal raphe,

Palego et al. (1999, 2000) have shown that 5-HT1A receptors

in human dorsal raphe can inhibit forskolin-stimulated AC,

so the lack of coupling of this receptor in the raphe may be

species specific.

The 5-HT1A receptor has been reported to couple po-

sitively to AC in the hippocampus (Markstein et al., 1986;

Shenker et al., 1987; Fayolle et al., 1988; Cadogan et al.,

1994) and the prostate. Some of these responses are possibly

due to confusion with another receptor subtype (Shenker

et al., 1987), most likely the 5-HT7 receptor subtype, which

can be stimulated by the 5-HT1A receptor-selective ligand

8-OH-DPAT. The 5-HT1A receptor in the ventral prostate

has been shown to slightly activate AC under very special

conditions (Carmena et al., 1998). 8-OH-DPAT, presumably

working through the 5-HT1A receptor, was shown to aug-

ment forskolin-stimulated cAMP accumulation, but only

after pretreatment of rats or their excised prostate glands

with 8-OH-DPAT. Because the effect was small, and

because no agents more specific than 8-OH-DPAT were

used, there remains the possibility that this effect was

mediated through the 5-HT7 receptor. However, in another

report, the authors used microdialysis to detect increases in

cAMP in response to 8-OH-DPAT in rat hippocampus, an

effect that they were able to attenuate with a selective

5-HT1A receptor antagonist (N-tert-butyl-3-(4-(2-methoxy-

phenyl)-piperazin-1-yl)-2-phenylpropanamide) (Cadogan

et al., 1994). Their report provided very tantalizing evidence

that the 5-HT1A receptor can activate AC.

This evidence was perplexing in light of a relatively

detailed study that could not detect coupling of the 5-HT1A

receptor to Gs or increased AC activity in CHO cells

(Raymond et al., 1993b). A recent study confirmed that

wild-type 5-HT1A receptors in HEK 293 cells do not

stimulate cAMP accumulation; they further demonstrated

that the carboxyl terminal region of the i3 loop of the

5-HT1A receptor could be mutated to induce only a very

weak coupling to Gs (Malmberg & Strange, 2000). There-

fore, if the 5-HT1A receptor couples positively to AC, it

would seem to require a highly specific cellular milieu,

perhaps necessitating the expression of particular subtypes

of AC. The family of ACs consists of at least nine distinct

members, each possessing a diverse repertoire of regula-

tory inputs (Mons et al., 1998; Taussig & Zimmermann,

1998; Hurley, 1999). Because the 5-HT1A receptor can

activate a multitude of signaling pathways, it could regu-

late AC in a number of ways, depending upon both the

specific signals generated by receptor occupancy and the


types and amounts of ACs expressed in the cells or tissues

of interest.

Three studies have suggested that the presence of AC2 is

a key determinant for the positive coupling of the 5-HT1A

receptor to cAMP accumulation. Uezono et al. (1993) used

the Xenopus oocyte system to show that b2-adrenergicreceptor increases in cAMP were enhanced by activation

of co-expressed 5-HT1A receptors. The additional activation

by the 5-HT1A receptor was enhanced by co-expression of

AC2, but not AC3 (Uezono et al., 1993). Liu et al. (1999)

showed that depletion of Gia1 from GH4 pituitary cells

switched the effect of the 5-HT1A receptor on cAMP accu-

mulation from an inhibitory to a stimulatory one. Moreover,

the stimulatory effect was sensitive to pertussis toxin, sug-

gesting that either a Gi- or Go-protein subtype specifically

mediates the effect. The same group performed more detailed

studies in HEK 293 cells, showing a requirement for AC2

and G-protein bg-subunits for the 5-HT1A receptor to

increase cAMP in an agonist-dependent fashion. Moreover,

they demonstrated that the 5-HT1A receptor also contributed

to agonist-independent increases in basal cAMP accumula-

tion that also depended upon Gia2 (Albert et al., 1999). Thus,

the 5-HT1A receptor can stimulate cAMP accumulation in

cells that express AC2 via release of bg-subunits from

pertussis toxin-sensitive G-proteins (probably Gia2).

2.1.2. The 5-hydroxytryptamine1A receptor activates and

inhibits phosphatidylinositol-specific phospholipase C

Activation of phosphatidylinositol-specific (PI)-PLC

results in the generation of two key second messengers.

These are inositol trisphosphate (IP3), which regulates in-

tracellular Ca2 + release (Berridge et al., 1998), and diacyl-

glycerol (DAG), which binds to and activates PKC. PLC

can be activated by receptors that couple to both pertussis

toxin-sensitive and -sensitive G-proteins. Although 5-HT1A

receptors can clearly activate PLC, this effect is highly host

cell-specific. The ability of the human 5-HT1A receptor to

activate PI-PLC was first demonstrated in transfection

studies in HeLa cells (Fargin et al., 1989). The stimulation

was similar in magnitude to that induced by endogenous

histamine H1-like receptors, but was not as efficient as

coupling of the 5-HT1A receptor to the inhibition of AC

(Raymond et al., 1991). The activation of PLC by the

human 5-HT1A receptor in HeLa cells was confirmed in

several other studies (Middleton et al., 1990; Boddeke et

al., 1992; Harrington et al., 1994). Liu and Albert (1991)

subsequently demonstrated that activation of PI-PLC by the

5-HT1A receptor is cell-specific. They showed that the rat

5-HT1A receptor increased PI hydrolysis and released Ca2 +

from intracellular stores in Ltk� fibroblasts, but not in

BALB/c-3T3 cells (Abdel-Baset et al., 1992) or in GH4C1

pituitary cells (Liu & Albert, 1991). The human 5-HT1A

receptor can also activate PLC when expressed in Xen-

opus oocytes (Ni et al., 1997). This coupling may be

relevant in that endogenous 5-HT1A receptors in a human

T-cell-like line (Jurkat) activate PLC (Aune et al., 1993).

In contrast, transfected 5-HT1A receptors do not stimulate

PLC in CHO cells (Newman-Tancredi et al., 1992; Cowen

et al., 1997), COS-7 cells (Fargin et al., 1989), or NIH 3T3

cells (Varrault et al., 1992a). It bears mentioning that the

5-HT1A receptor has also been shown to inhibit PLC

activation in rat hippocampal preparations (Claustre

et al., 1991), although this effect was not sensitive to

pertussis toxin.

2.1.3. The 5-hydroxytryptamine1A receptor activates

other phospholipases

The 5-HT1A receptor probably can regulate PLs other than

PI-PLC. Cowen et al. (1997) proposed that the 5-HT1A

receptor activates a phosphatidylcholine-specific (PC)-PLC

in CHO cells, and that this activity may be important in the

regulation of nuclear factor-kB and extracellular signal-

regulated kinase (ERK). Their data showed that 8-OH-

DPAT elicited release of 3H from cells preloaded with

[3H]choline. This effect was attenuated by a PC-PLC

inhibitor (tricyclodecan-9-yl-xanthogenate). The 5-HT1A

receptor in rat hippocampus has been proposed to stimulate

PLA2 based on inhibitor studies (Claustre et al., 1991). The

recombinant 5-HT1A receptor has also been shown to

activate PLA2 in HeLa cells (Harrington et al., 1994), and

to augment Ca2 +-induced AA metabolism in CHO cells

(Raymond et al., 1992). In contrast, 5-HT1A receptor ago-

nists attenuate N-methyl-D-aspartic acid (NMDA) receptor-

evoked AA release in adult rat hippocampus, raising the

possibility that the 5-HT1A receptor might inhibit PLA2 in

some settings (Strosznajder et al., 1996).

2.1.4. The 5-hydroxytryptamine1A receptor activates protein

kinase C

The 5-HT1A receptor activates several different protein

kinases. These include serine-threonine, tyrosine, and

lipid kinases. Not surprisingly, the 5-HT1A receptor can

activate PKC in cells in which the receptor has been

shown to stimulate PLC (Raymond et al., 1989; Mid-

dleton et al., 1990; Liu & Albert, 1991). This is not

surprising, in that PKC can be activated by Ca2 + and

DAG (Tanaka & Nishizuka, 1994; Nishizuka, 1995).

Activation of PKC by the 5-HT1A receptor depends upon

PLC activation. As this effect is probably mediated by

G-protein bg-subunits, it will depend upon the expres-

sion of bg-regulated PLC in the target cell or tissue. The

coupling of the 5-HT1A receptor to PKC is as efficacious

as that induced by the endogenous histamine receptor

expressed in HeLa cells.


the extracellular signal-regulated mitogen-activated

protein kinase

Several groups have documented that the 5-HT1A recep-

tor activates ERK MAP kinases in CHO cells (Cowen, D. S.

et al., 1996; Garnovskaya et al., 1996, 1998; Della Rocca

et al., 1999; Mendez et al., 1999; Mukhin et al., 2000). Like


other GPCRs, the 5-HT1A receptor activates ERK through

an intricate signaling pathway that involves assembly of a

signaling complex that requires many of the same mole-

cules used by growth factor receptor tyrosine kinases

(Marshall, 1995; Luttrell et al., 1997). The activation of

ERK by the 5-HT1A receptor is initiated by bg-subunitsreleased from pertussis toxin-sensitive G-proteins. This

results in activation of the non-receptor tyrosine kinase

Src and tyrosine phosphorylation of the docking platform

Shc. Shc phosphorylation results in the recruitment of

PI-30 kinase, Grb2 (an adapter protein), and a Ras act-

ivator protein called Sos to the signaling platform. Ras

activation leads to sequential activation of Raf, mitogen

and extracellular signal-regulated kinase (MEK) and ERK

(Cowen, D. S. et al., 1996; Garnovskaya et al., 1996, 1998;

Mendez et al., 1999). Cowen, D. S. et al. (1996) hypothe-

sized that PC-PLC augments the activation of Raf that is

induced by Ras. Thus, it is possible that the 5-HT1A receptor

in CHO cells activates ERK through the two converging

lipid-signaling pathways. The first involves PI-30 kinase and

intersects the ERK pathway upstream of Ras, whereas the

second involves PC-PLC and intersects the ERK pathway

upstream of Raf.

Other studies have implicated a Ca2 +/calmodulin (CaM)-

dependent endocytosis step between Ras and Raf (Della

Rocca et al., 1999) and reactive oxygen species (H2O2 and

superoxide) upstream of Src in 5-HT1A receptor-mediated

ERK activation in CHO cells (Mukhin et al., 2000).

Although the coupling of the 5-HT1A receptor to ERK has

been relatively well characterized in CHO cells, studies in

other cells or tissues are still needed.

2.1.6. The 5-hydroxytryptamine1A receptor stimulates

phosphatidylinositol-30 kinase

The ability of the 5-HT1A receptor expressed in CHO

cells to activate ERK (Cowen, D. S. et al., 1996; Garnov-

skaya et al., 1996, 1998) and Na + -proton exchange (Gar-

novskaya et al., 1998) is sensitive to pharmacological

inhibitors and cDNA constructs encoding dominant inter-

fering p85 and p110 subunit of PI-30 kinase. Moreover,

Adayev et al. (1999) showed that the 5-HT1A receptor can

stimulate PI-30 kinase-g in HN2-5 cells.

2.1.7. The 5-hydroxytryptamine1A receptor causes

production of reactive oxygen and nitrogen species

The 5-HT1A receptor in CHO cells has been shown by

inhibitor, biochemical, and fluorometric methods to stimu-

late production of at least two reactive oxygen species, H2O2

and superoxide (Mukhin et al., 2000). The production of

these reactive oxygen species by the 5-HT1A receptor

appears to occur at a point upstream of Src, and involves

an NAD(P)H oxidase-like enzyme. Activation of this

enzyme and the resulting production of reactive oxygen

species is a critical step in the stimulation of ERK phospho-

rylation and kinase activity by the human 5-HT1A receptor

(Mukhin et al., 2000).

The 5-HT1A receptor can also regulate the production of

nitric oxide (NO), although there is no consensus on

whether the major effect is to stimulate or inhibit its

production. There is tantalizing evidence that the 5-HT1A

receptor can increase NO production in at least three

settings. First, 8-OH-DPAT-associated hyperphagia in rats

(routinely attributed to the 5-HT1A receptor) can be inhi-

bited by NOS inhibitors (Yamada et al., 1996; Sugimoto

et al., 1999a, 1999b). Second, putative 5-HT1A receptor-

induced renal vasodilatory effects have been ascribed to the

release of NO from endothelial cells in the renal micro-

circulation (Verbeuren et al., 1991; Verbeuren, 1993).

Third, in a single report, putative endogenous 5-HT1A

receptors in rat ventral prostate cells were shown to

stimulate NOS activity (Carmena et al., 1998). In contrast,

there is evidence that the 5-HT1A receptor can inhibit

NMDA-induced NO production in human neocortical sli-

ces (Maura et al., 2000) and in adult rat hippocampus

(Strosznajder et al., 1996), and that it can inhibit NMDA/

a-amino-3-hydroxy-5-methyl-isoxazole-4-propionate re-

ceptor-induced cyclic GMP (cGMP) accumulation (a par-

ticipant in the NO pathway) in rat cerebellar synaptosomes

(Maura & Raiteri, 1996). Clearly, more studies are needed

in this area.

2.1.8. The 5-hydroxytryptamine1A receptor regulates

K+ channels

The 5-HT1A receptor has been shown to regulate the

function of several distinct types of channels, including

inwardly rectified K + channels, high conductance anion

channels, cystic fibrosis transmembrane regulator Cl– chan-

nels, and Ca2 + channels. It has been known for at least

15 years that the 5-HT1A receptor can stimulate the opening

of G-protein-gated inwardly rectifying K + (GIRK) channels

in neurons (Andrade & Nicoll, 1987; Colino & Halliwell,

1987; Zgombick et al., 1989; Penington et al., 1993;

Doupnik et al., 1997). Those channels mediate hyperpolar-

izing postsynaptic potentials in the nervous system and in

the heart during activation of Gi/oa-coupled receptors. The

regulation of GIRK channels by receptors relies upon the

interaction of G-protein bg-subunits (Doupnik et al., 1996,

1997). The 5-HT1A receptor expressed in primary cultures

of rat atrial myocytes with a Vaccinia virus vector stimulates

an endogenous atrial inward rectifier K + current (Karschin

et al., 1991). Co-injection of rat atrial RNA, GIRK1 RNA,

or rat brain GIRK3 with 5-HT1A receptor RNA into Xen-

opus oocytes resulted in 5-HT1A receptor stimulation of

GIRK activity (Dascal et al., 1993; Dissmann et al., 1996;

Doupnik et al., 1997). An additional intriguing finding is

that various regulators of G-protein signaling (RGS) pro-

teins (RGS1, RGS3, and RGS4, but not RGS2) participated

in the functional regulation of 5-HT1A receptor-mediated

GIRK activation (Doupnik et al., 1997).

The 5-HT1A receptor, however, does not universally

stimulate inwardly rectified K + channels in all cell types.

When co-expressed by transfection into COS-7 cells, the


5-HT1A receptor inhibited the cloned rat, strongly rectify-

ing the inward rectifier K + (IRK)-type inwardly rectifying

K + channel IRK1 (Kir 2.1). The inhibition was mimicked

by elevations of internal cAMP concentrations and by

microinjection of the catalytic subunits of protein kinase

A (PKA), and was not present when mutant IRK1 chan-

nels lacking a PKA phosphorylation site were studied

(Wischmeyer & Karschin, 1996). These results suggest

that the 5-HT1A receptor can inhibit IRK channels, and

support a possible role for this receptor in stimulating

cAMP production in COS-7 cells (see Section 2.1.1).

2.1.9. The 5-hydroxytryptamine1A receptor inhibits neuronal

Ca2+ conductances

The 5-HT1A receptor has been demonstrated to inhibit a

Ca2 + current in neurons (Penington & Kelly, 1990) and

neuronal cell lines (Singh et al., 1996). These effects have

been attributed to inhibition of both N- and P/Q-type Ca2 +

channels (Penington et al., 1991; Bayliss et al., 1995; Sun

& Dale, 1998). For example, the 5-HT1A receptor in

X. laevis spinal neurons causes voltage-independent inhibi-

tion of V-agatoxin-IVA-sensitive (P/Q-type) Ca2 + channels

(Sun & Dale, 1998). Liu et al. (1994) confirmed that the

rat 5-HT1A receptor inhibited Bay K8644-mediated Ca2 +

influx when transfected in GH4C1 cells, and further dem-

onstrated that this effect required expression of Goa. The

involvement of G-proteins in the inhibition of Ca2 +

currents was confirmed by studies showing that a peptide

inhibitor of G-protein bg-subunit attenuated 5-HT1A recep-

tor-mediated inhibition of Ca2 + current in dorsal raphe

neurons (Chen & Penington, 1997).

2.1.10. The 5-hydroxytryptamine1A receptor regulates other

ion channels

The 5-HT1A receptor has been shown to regulate several

other channels in transfected cells. Ni et al. (1997) dem-

onstrated that the 5-HT1A receptor expressed in Xenopus

oocytes could stimulate an oscillatory Ca2 + -activated Cl–

current, although this effect was much less efficient than

that associated with the 5-HT2C receptor. Uezono et al.

(1993) showed that the 5-HT1A receptor expressed in

Xenopus oocytes could indirectly augment the activation

of cystic fibrosis transmembrane regulator Cl– channels

induced by b2-adrenoceptors. This effect likely proceeded

via G-protein bg-subunits, and was enhanced by co-expres-

sion of AC2 and Gsa (Uezono et al., 1993). The 5-HT1A

receptor expressed by transfection in CHO cells inhibits an

endogenous high-conductance anion channel through either

Gia2 or Gia3.


miscellaneous transport processes

The 5-HT1A receptor has been shown to regulate

several transport processes in transfected cells and native

tissues. The 5-HT1A receptor stimulates Na + /K + -ATPase

through a Ca2 + -mediated pathway (Middleton et al., 1990)

and Na + -dependent phosphate uptake through a PKC-

mediated pathway (Raymond et al., 1989, 1991) in HeLa

cells. In CHO cells, the 5-HT1A receptor stimulates an

Na + /H + exchanger (Garnovskaya et al. 1997, 1998)

through a pathway that requires Gia2 and/or Gia2, Src,

and PI-30 kinase (Garnovskaya et al., 1997, 1998). The

activation of Na + -dependent phosphate uptake suggests a

potential role for the 5-HT1A receptor in regulating cellular

energy fluxes, whereas the coupling to Na + /K + -ATPase

and Na + /H + exchange suggests potential roles in cell

volume regulation. The 5-HT1A receptor in CHO cells has

also been demonstrated to accelerate mediator-facilitated

electron fluxes across the plasma membrane, a process that

may be linked to the production of reactive oxygen species

(Mukhin et al., 2000).

The 5-HT1A receptor can also regulate 5-HT, norepi-

nephrine, and acetylcholine release from neurons. Release

of 5-HT involves presynaptic receptors (Verge et al., 1985,

1986; Sharp & Hjorth, 1990), whereas release of norepi-

nephrine (Done & Sharp, 1994; Chen & Reith, 1995) and

acetylcholine (Bianchi et al., 1990; Izumi et al., 1994)

involves postsynaptic receptors (Hall et al., 1985; Verge

et al., 1986).


proliferation and related pathways

The 5-HT1A receptor can stimulate proliferative and

mitogenic pathways in various cell systems, consistent with

its stimulation of ERK (see Section 2.1.5) and nuclear

factor-kB (Cowen et al., 1997). 5-HT1A receptors stimulate

proliferation of T lymphocytes (Iken et al., 1995), pancreatic

carcinoid tumor cells (Ishizuka et al., 1992), and human

small cell lung carcinoma cells (Cattaneo et al., 1995).

Activation of 5-HT1A receptors expressed in NIH 3T3 cells

induces focus formation and potentiates the stimulation of

DNA synthesis by epidermal growth factor (Varrault et al.,

1992a). Rat 5-HT1A receptors transfected into BALB/c-3T3

cells enhance thymidine uptake and induce focus formation

(Abdel-Baset et al., 1992). All of those studies are consistent

with a stimulatory effect of the 5-HT1A receptor on prolif-

eration. However, this is not a universal effect in that

endogenous 5-HT1A receptors in lymphocytes have been

implicated in the inhibition of mitogenic responses (Ferriere

et al., 1996).

The 5-HT1A receptor has also been implicated in morpho-

genesis and cell survival. Blockade of endogenous 5-HT1A

receptors reverses serotoninergic stimulation of tooth germ

development in mouse mandibular explant cultures (Moi-

seiwitsch et al., 1998), suggesting a developmental role for

this receptor. Transfected 5-HT1A receptors have been

shown to inhibit a caspase 3-like enzyme and to attenuate

(by � 60–70%) anoxia-induced apoptosis in the neuronal

HN2-5 cells via an ERK-dependent pathway (Adayev et al.,

1999), suggesting a potential role for the 5-HT1A receptor

in neuronal survival.


2.1.13. What is the basis for the multiplicity of

5-hydroxytryptamine1A receptor signaling?

This question is worth addressing briefly, as it is pertinent

to all of the 5-HT receptors from the GPCR family. Many

possible explanations for the multiplicity of signaling mech-

anisms of the 5-HT receptors to diverse signaling pathways

could be proposed. These include the ability to activate

overlapping pools of G-proteins, activation of distinct sig-

nals emanating from G-protein a- and bg-subunits, differingrepertoires of G-proteins and signaling enzymes expressed in

cells, ratio of G-protein/effector/and receptor, ligand-specific

effects, differential rates of desensitization, and cellular

compartmentalization, to name just a few. This issue has

been reviewed in detail (Raymond, 1995).

In that regard, the 5-HT1A receptor has been identified in

both presynaptic and postsynaptic locations (Miquel et al.,

1992; Radja et al., 1992). The signaling properties and

pharmacology of the presynaptic and postsynaptic 5-HT1A

receptors vary somewhat (Clarke et al., 1996), leading to

speculation that there might be subtypes of 5-HT1A recep-

tors (Barnes & Sharp, 1999). Langlois et al. (1996) dem-

onstrated that 5-HT1A receptors transfected into polarized

epithelial LLC-PK1 cells were expressed on both baso-

lateral and apical membranes. Receptors on both surfaces

were able to inhibit cAMP accumulation, albeit with

different efficiencies (Langlois et al., 1996). This study

demonstrates that the variables that affect the multiplicity of

signaling from single receptor types are not likely to be

manifested as ‘‘all or none’’ effects. Thus, the specific

coupling of single types of 5-HT receptors to signaling

pathways is likely to result from the summation of effects

specific to the host cell milieu.

One other theoretical possibility is that some signals

emanating from 5-HT1A (or other 5-HT) receptors may

be regulated by effector pathways activated through non-

G-protein-activated pathways. This intriguing hypothesis

has been reviewed recently by Hall et al. (1999).

2.2. The 5-hydroxytryptamine1B receptor

The 5-HT1B receptor initially was identified as a low-

affinity [3H]spiperone-binding site (Nelson et al., 1981;

Pedigo et al., 1981), distinguishing it from the 5-HT1A

receptor. There has been considerable confusion over the

identities of the 5-HT1B and 5-HT1D receptors. Thus, a brief

history of these two closely related receptor subtypes is in

order. It originally was thought that the 5-HT1B receptor was

primarily or exclusively expressed in rodent (hamster,

mouse, and rat) tissues, whereas the closely related

5-HT1D receptor was believed to be expressed in other

species (humans, cows, dogs, and guinea pigs) (Hoyer &

Middlemiss, 1989). The two receptors are pharmacolo-

gically similar, although not identical. The major pharmaco-

logical distinction is that b-adrenergic receptor antagonists

bind with high affinity to the 5-HT1B receptor, but not to the

5-HT1D receptor. Because the distributions of the 5-HT1D

and the rodent 5-HT1B receptors showed significant overlap,

Hoyer and Middlemiss (1989) initially proposed that the

two were species homologues.

The subsequent identification of two intronless human

receptor genes encoding 5-HT receptors with pharmaco-

logical characteristics similar to the 5-HT1D receptor

resulted in their temporary designation as 5-HT1D receptors

(5-HT1Da and 5-HT1Db) (Hamblin & Metcalf, 1991; Ham-

blin et al., 1992; Hartig et al., 1992; Weinshank et al., 1992).

The cloning and identification of the rodent 5-HT1B receptor

cDNA and gene revealed a surprisingly high homology with

the human 5-HT1Db receptor (Voigt et al., 1991; Adham

et al., 1992; Jin et al., 1992; Maroteaux et al., 1992).

Whereas the human 5-HT1Da and 5-HT1Db receptors share

77% sequence homology in the transmembrane domains,

the human 5-HT1Db and rodent 5-HT1B receptors share 96%

homology (Hartig et al., 1992; Jin et al., 1992). The

uniquely high affinity of the rodent 5-HT1B receptors for

b-adrenergic receptor antagonists when compared with the

human 5-HT1Db receptors was shown to depend upon a

single amino acid residue difference (Metcalf et al., 1992;

Oksenberg et al., 1992; Parker et al., 1993). Subsequently,

the cloning by Hamblin and colleagues (1992) of a rat gene

that encodes a 5-HT receptor with pharmacological charac-

teristics more closely resembling the 5-HT1D receptor than

the 5-HT1B receptor gave further support to the idea that the

5-HT1B and 5-HT1D receptors represent separate gene

products that are not exclusively expressed in rodent or

non-rodent mammals. The preponderance of evidence

resulted in a reassessment of the nomenclature of these

receptors in which the human 5-HT1Da and rodent 5-HT1D

receptors were reclassified as 5-HT1D receptors, and the

human 5-HT1Db and all 5-HT1B receptors were classified as

5-HT1B receptors (Hartig et al., 1996).

The 5-HT1B receptor is widely expressed in brain

tissue, probably in both presynaptic and postsynaptic

locations (Middlemiss & Hutson, 1990; Buhlen et al.,

1996). The 5-HT1B receptor gene is located on chromosome

6q13 in humans and chromosome 9E in mice (Saudou &

Hen, 1994). The human gene encodes a protein with 390

amino acids.

2.2.1. The 5-hydroxytryptamine1B receptor regulates

adenylyl cyclase

In general, all of the 5-HT1 receptors can be expected to

share many of the signaling linkages of the 5-HT1A receptor

(Hoyer et al., 1994). Thus, the 5-HT1B receptor would be

expected to couple mainly to pertussis toxin-sensitive

G-proteins and to inhibit AC. The 5-HT1B receptor, in fact,

has been shown to inhibit AC when natively expressed in

tissues such as the substantia nigra (Bouhelal et al., 1988;

Schoeffter et al., 1988) and rabbit mesenteric artery (Hinton

et al., 1999), in opossum kidney cells (Ciaranello et al.,

1990; Zgombick & Branchek, 1998), human umbilical

endothelial vein cells (Schoeffter et al., 1995), bovine

basilar artery vascular smooth muscle cells (Ebersole et al.,


1993), or CHO-K1 cells (Berg et al., 1994b; Giles et al.,

1996), and when heterologously expressed in transfected

cells (Ltk-, COS-7, Sf9 cells) (Adham et al., 1992; Levy

et al., 1992b; Weinshank et al., 1992; Ng et al., 1993). Like

the 5-HT1A receptor, the 5-HT1B receptor has also been

documented to increase cAMP in HEK 293 cells through a

conditional process that involves ACII and Gi proteins

(Albert et al., 1999).

The 5-HT1B receptor has been shown to couple to

mammalian Gi/o-proteins in Sf9 cells when expressed using

a Baculovirus vector. Slightly different coupling efficiencies

were noted, such that high-affinity agonist binding to the

5-HT1B receptor was stimulated with the following rank

order: Gia3 > Gia1 � Gia2 � Goa (Clawges et al., 1997).

The same group noted that the 5-HT1A receptor coupled to

the G-proteins slightly more efficiently than the 5-HT1B

receptor. Although the G-protein coupling in Sf9 cells was

slightly more efficient for the 5-HT1A receptor than for the

5-HT1B receptor, another group showed that lower numbers

of transfected 5-HT1B receptors than 5-HT1A receptors were

needed for efficient inhibition of AC when transfected into

mammalian cells (Mendez et al., 1999).

2.2.2. The 5-hydroxytryptamine1B receptor

activates phospholipases

The 5-HT1B receptor can activate PLC in several cell

types. This effect is manifested by pertussis toxin-sensitive

increases in intracellular Ca2 + in opossum kidney cells

(Zgombick & Branchek, 1998). Although 5-HT1B receptors

natively expressed in CHO cells were not shown to increase

accumulation of inositol phosphates (Dickenson & Hill,

1995), transfected human 5-HT1B receptors were shown to

mediate pertussis toxin-sensitive increases in both intra-

cellular Ca2 + and accumulation of inositol phosphates in

CHO cells through G-proteins and PLC (Dickenson & Hill,

1998). The 5-HT1B receptor in vascular smooth muscle

cells derived from bovine basilar artery also increases

intracellular Ca2 + through a pertussis toxin-sensitive mech-

anism (Ebersole et al., 1993), and this signal may be

responsible for 5-HT1B-induced blood vessel contractions

(Ullmer et al., 1995).

5-HT can also stimulate PLD via endogenous 5-HT1B

receptors in rabbit mesenteric artery through a signaling

pathway that requires extracellular Ca2 + and the activa-

tion of PKC, but is independent of PLC activation (Hinton

et al., 1999).


the extracellular signal-regulated kinase,

phosphatidylinositol-30 kinase,

p70 S6 kinase, and Akt kinase

Over a decade ago, endogenous 5-HT1B receptors in

fibroblasts were reported to stimulate DNA synthesis

through a pertussis toxin-sensitive pathway that does not

involve PLC (Seuwen et al., 1988). Subsequent studies have

revealed that the 5-HT1B receptor can activate ERK in

bovine aortic endothelial cells (McDuffie et al., 2000),

BE2-C neuroblastoma cells (Lione et al., 2000), and CHO

cells (Pullarkat et al., 1998; Mendez et al., 1999). In CHO

cells, this occurs through a pathway that involves pertussis

toxin-sensitive G-proteins, PI-30 kinase, and MEK (Pullarkat

et al., 1998; Mendez et al., 1999). Akt kinase is also

activated by 5-HT1B receptors acting through pertussis

toxin-sensitive G-proteins in BE2-C neuroblastoma cells

(Lione et al., 2000). In CHO cells, 5-HT1B receptors activate

p70 S6 kinase through a pathway that involves PI-30 kinase

and MEK, and is sensitive to rapamycin and pertussis toxin.

Interestingly, coupling to ERK of the 5-HT1B receptor in

CHO cells was shown to be relatively more efficient than

that induced by the 5-HT1A receptor (Mendez et al., 1999).

2.2.4. The 5-hydroxytryptamine1B receptor stimulates

endothelial nitric oxide production

The 5-HT1B receptor increases NO in cultured human

coronary artery rings (Auch-Schwelk et al., 2000) and

endothelial cells, probably through increasing levels of

intracellular Ca2 + (Ishida et al., 1998). McDuffie et al.

(1999) presented evidence that the 5-HT1B receptor stim-

ulates endothelial NOS through pertussis toxin-sensitive

G-proteins in cultured bovine aortic endothelial cells. This

signaling pathway (and another linked to 5-HT2B receptors)

probably accounts for most of the 5-HT-induced vasorelax-

ation in diverse vascular beds (Ullmer et al., 1995).

2.2.5. Other signals of the 5-hydroxytryptamine1B receptor

Several groups have demonstrated that presynaptic

5-HT1B receptors decrease 5-HT release (Sharp et al., 1989;

Hjorth & Tao, 1991; Lawrence & Marsden, 1992; Martin

et al., 1992; Davidson & Stamford, 1996). Human 5-HT1B

receptors stably transfected in C6 glioma cells activate

Ca2 + -dependent K + channels (Le Grand et al., 1998).

2.3. The 5-hydroxytryptamine1D receptor

The 5-HT1D receptor was discovered by homology

screening using the canine RDC4 gene. That screen

revealed two similar genes with pharmacology closely

linked to each other, which were originally termed 5-HT1Da

and 5-HT1Db. These were later reclassified respectively as

the 5-HT1D and 5-HT1B receptors (see Section 2.2). The

gene is intronless, is located on chromosome 1p34.3, and

encodes a protein of 377 amino acids. The 5-HT1D receptor

shares 43% sequence homology with the 5-HT1A receptor

and 59% with the 5-HT1B receptor (77% in the transmem-

brane regions) (Hamblin & Metcalf, 1991; Hamblin et al.,

1992; Hartig et al., 1992).

It has been difficult to establish the precise locations of

5-HT1D receptors due to the lack of specific ligands and

apparently low levels of mRNA and receptor protein in the

brain. Binding sites for the 5-HT1D receptor have localized

to the substantia nigra, globus pallidus, and caudate, and in

lower levels in the cortex and hippocampus putamen


(Bruinvels et al., 1993), although mRNA for this receptor

was not detected in the globus pallidus or substantia nigra

(Bruinvels et al., 1994a, 1994b). These results suggest that

5-HT1D receptors may be transported along axon terminals

after their synthesis.

2.3.1. The 5-hydroxytryptamine1D receptor inhibits

adenylyl cyclase

As has been shown for all other 5-HT1 receptors, the

5-HT1D receptor can inhibit AC through pertussis toxin-

sensitive G-proteins in transfected C6 glioma and NIH 3T3

fibroblast cells (Maenhaut et al., 1991; Weinshank et al.,

1992; Zgombick et al., 1996; Lesage et al., 1998). How-

ever, when expressed at high levels in CHO or Y1 adrenal

cells, this receptor can also weakly stimulate cAMP

accumulation (Van Sande et al., 1993; Watson et al.,

1996; Wurch et al., 1997).

2.3.2. The 5-hydroxytryptamine1D receptor regulates

ion channels

Like other 5-HT1 receptors, the 5-HT1D receptor can

regulate K + and Ca2 + channels. In Xenopus spinal

neurons, the 5-HT1D receptor was reported to cause

voltage-independent inhibition of V-conotoxin-GVIA-sens-

itive (N-type) Ca2 + channels (Sun & Dale, 1998),

although the ligands used were not sufficiently discrim-

inative to rule out the involvement of 5-HT1B receptors

in mediating this effect. Like 5-HT1B receptors, recombin-

ant human 5-HT1Dreceptors stably transfected in C6

glioma cells can stimulate Ca2 + -dependent K + channels,

with the resultant outward hyperpolarizing current being

dependent upon IP3 receptor-mediated intracellular Ca2 +

release (Le Grand et al., 1998).

2.3.3. The 5-hydroxytryptamine1D receptor is mitogenic

5-HT1D receptors endogenous to two small cell lung

carcinoma cell lines (GLC8 and NCI-N-592) have been

reported to stimulate DNA synthesis, although effects of

5-HT1B receptors were not ruled out (Cattaneo et al., 1994).

However, cloned human 5-HT1D receptors transfected into

C6 glial cells promote cell growth, so there is little doubt

that the 5-HT1D receptor (like 5-HT1A and 5-HT1B recep-

tors) can be mitogenic (Pauwels et al., 1996).

2.3.4. The 5-hydroxytryptamine1D receptor inhibits

5-hydroxytryptamine release

5-HT1D receptors can inhibit 5-HT release in several

brain regions. 5-HT efflux in the ventral lateral geniculate

nucleus of the rat is modulated by presynaptic 5-HT1D

receptors (Davidson & Stamford, 1996). 5-HT1D autorecep-

tors diminish 5-HT release in guinea-pig mesencephalic

raphe, hippocampus, and frontal cortical slices through a

pathway involving G-proteins. Interestingly, 5-HT1B recep-

tors did not decrease 5-HT release in this preparation

(el Mansari & Blier, 1996). In contrast, Trillat et al.

(1997) showed that the inhibition of cortical and hippo-

campal 5-HT release was absent in 5-HT1B receptor knock-

out mice. Thus, the respective roles of the 5-HT1B and

5-HT1D receptors in the inhibition of 5-HT release remain

unresolved in many brain regions.

Inhibition of glutamate release from rat cerebellar

synaptosomes and from human neocortex is attributable

to 5-HT1D receptors (Raiteri et al., 1986; Maura & Raiteri,

1996; Maura et al., 1998). Molderings et al. (1996)

demonstrated that presynaptic 5-HT1D receptors can inhibit

norepinephrine release from isolated human right atrial

appendage sections.

2.4. The 5-hydroxytryptamine1E receptor

The 5-HT1E receptor originally was identified as a

component of [3H]5-HT binding to human cortical homo-

genates that was resistant to a cocktail of antagonists of

5-HT1A, 5-HT1B/D, and 5-HT2 receptors (Leonhardt et al.,

1989). The intronless 5-HT1E receptor gene was subse-

quently cloned from human and rat (Levy et al., 1992a;

McAllister et al., 1992; Zgombick et al., 1992; Lovenberg

et al., 1993b). The human gene encodes a protein of 365

amino acids. This protein shares 39% homology with the

5-HT1A receptor and 47% identity (64% in the transmem-

brane regions) with the 5-HT1B/D receptors. The 5-HT1E

receptor gene has been localized to human chromosome

6q14-q15 (Levy et al., 1994).

There are few details about signaling pathways linked to

the 5-HT1E receptor. Low concentrations of agonist have

been shown to inhibit AC in HeLa and BS-C-1 cells trans-

fected with the 5-HT1E receptor (Lovenberg et al., 1993b;

Adham et al., 1994). The 5-HT1E receptor can also stimulate

AC, as high concentrations of agonist also promote

increases in cAMP in BS-C-1 cells (Adham et al., 1994).

The 5-HT1E receptor has not yet been demonstrated to

stimulate PLC and/or PLA2. In BS-C-1 cells, 5-HT had no

effect on inositol phosphate release, intracellular Ca2 +

levels, or AA mobilization (Adham et al., 1994).

2.5. The 5-hydroxytryptamine1F receptor

The 5-HT1F receptor originally was cloned from

mouse, and was termed 5-HT1Eb, based on pharmaco-

logical similarities with the 5-HT1E receptor (Amlaiky

et al., 1992). The human gene is intronless like the mouse

gene, and it is located on chromosome 3q11 (Saudou &

Hen, 1994).

The 5-HT1F receptor gene encodes a protein of 366

amino acids, with 70% homology to the 5-HT1E receptor,

60% to the 5-HT1B receptor (60%), and 63% to the 5-HT1D

receptor. 5-HT1F receptor mRNA was detected in human

brain, uterus, and mesentery, but not in kidney, liver, spleen,

heart, pancreas, and testes (Adham et al., 1993b). When

stably expressed in NIH 3T3 cells, the 5-HT1F receptor

negatively couples to AC (Amlaiky et al., 1992; Adham

et al., 1993b).


The 5-HT1F receptor has been shown to couple to PI-PLC

in a cell-specific manner. When transfected into NIH 3T3

cells, no elevation of inositol phosphates or Ca2 + was

observed, whereas in LM(tk-) cells, the receptor stimulated

accumulation of inositol phosphates and induced a rapid

increase of Ca2 + . PLC activation was blocked by pertussis

toxin, supporting a role for the Gi/o-protein (Adham et al.,

1993a). The significance of the coupling to PLC is uncertain,

as the transfected cells used in this study expressed high

levels of receptors (4.4 pmol/mg of protein). The 5-HT1F

receptor has been demonstrated to decrease capsaicin-

induced c-fos expression in the rat trigeminal nucleus

caudalis, although the signaling pathway of this effect was

not defined (Mitsikostas et al., 1999).


There are three members of the 5-HT2A receptor family,

termed 5-HT2A, 5-HT2B, and 5-HT2C (Hoyer et al., 1994).

The 5-HT2A receptor is probably the 5-HT M receptor

described by Gaddum and Picarelli (1957). The 5-HT2B

receptor was formerly referred to as the 5-HT2F receptor

[or serotonin receptor like (SRL)] (Foguet et al., 1992b),

and the 5-HT2C receptor was previously referred to as the

5-HT1C receptor. The 5-HT2 receptors couple consistently

to the PLC-b second messenger pathway (Peroutka, 1995)

in native tissues (Conn & Sanders-Bush, 1984) and hetero-

logous cells (Pritchett et al., 1988). Like the 5-HT1 recep-

tors, the 5-HT2 receptors can couple to other second

messenger pathways in a cell-specific manner. Unlike the

5-HT1 receptors, the 5-HT2 receptor genes have introns.

Although the 5-HT2 receptors are similar in structure,

pharmacology, and signaling pathways, there are a few

differences in their signaling properties (Berg et al., 1994b,

1996; Grotewiel & Sanders-Bush, 1999). These differences

will be discussed in Sections 3.1–3.3.

3.1. The 5-hydroxytryptamine2A receptor

The 5-HT2A receptor originally was identified as a

[3H]spiperone-binding site, with low affinity for 5-HT

(Leysen et al., 1978; Peroutka & Snyder, 1979). It was

classified as a 5-HT receptor based on pharmacological

similarities with other 5-HT receptors. The rat receptor

gene was identified in 1988 by Pritchett et al., and the

human receptor gene was identified in 1990 by Julius et al.

The rat and human genes are 87% homologous. The

human 5-HT2A receptor gene is located on chromosome

13q14-q21 (Hsieh et al., 1990). The 5-HT2A receptor

shares 45% homology with the 5-HT2B receptor and

49% homology with the 5-HT2C receptors (80% in the

transmembrane regions). The 5-HT2A receptor is widely

distributed in the brain (cortex, caudate nucleus, olfactory

tubercle, nucleus accumbens, and hippocampus) (Pazos et al.,

1985), skeletal (Guillet-Deniau et al., 1997; Hajduch et al.,

1999) and smooth muscle (Kuemmerle et al., 1995; Ellwood

& Curtis, 1997), kidneys (Garnovskaya et al., 1995), and

platelets (Cook et al., 1994).


phospholipase C

The 5-HT2A receptor activates PLC-b in most tissues and

cells in which it is expressed, resulting in accumulation of

inositol phosphates and elevations of intracellular Ca2 +

(Conn & Sanders-Bush, 1984, 1985; Roth et al., 1984,

1986; Tamir et al., 1992; Berg et al., 1998; Briddon et al.,

1998; Grotewiel & Sanders-Bush, 1999). These effects can

result in activation of L-type Ca2 + channels (Watts, 1998)

and stimulation of PKC (Takuwa et al., 1989).


other phospholipases

The 5-HT2A receptor activates other PLs, such as PLA2

and PLD. 5-HT2A receptors in CHO cells and 1C11 cells

activate PLA2-mediated AA release (Berg et al., 1996, 1998;

Tournois et al., 1998). In C6 glial cells, the 5-HT2A receptor is

coupled to themobilization of polyunsaturated fatty acids and

AA (Garcia & Kim, 1997). 5-HT2A receptor-induced pros-

taglandin release is thought to play a major role in the

acceleration of gastrointestinal transit (Matsuda et al.,

2000). The 5-HT2A receptor stimulates amyloid precursor

protein ectodomain secretion by a PLA2-dependent pathway

(Nitsch et al., 1996).

The 5-HT2A receptor has been shown to couple to

PLD in cultured rat renal mesangial cells (Kurscheid-

Reich et al., 1995). This effect is cell-specific, as the re-

ceptor does not couple to PLD in guinea pig trachea (Cox

et al., 1996).

3.1.3. The 5-hydroxytryptamine2A receptor can regulate

cyclic AMP accumulation in certain cells

The 5-HT2A receptor does not typically regulate cAMP

formation in most cells or tissues (Lucaites et al., 1996), but

it can both stimulate and diminish cAMP accumulation

in specific cell types. Berg et al. (1994a) showed that the

5-HT2A receptor can amplify cAMP formation in A1A1

cells by the intermediate actions of PKC-a and/or PKC-dand Ca2 + /CaM. In FRTL-5 thyroid cells, the 5-HT2A

receptor increases cAMP through a pertussis toxin-sensitive

mechanism (Tamir et al., 1992).

Garnovskaya et al. (1995) demonstrated that the 5-HT2A

receptor in rat renal mesangial cells could inhibit forskolin-

stimulated cAMP accumulation in intact cells and AC

activity in washed membranes. The inhibition of cAMP

accumulation did not involve PLC, Ca2 + , or PKC, but was

sensitive to pertussis toxin, suggesting that the 5-HT2A

receptor in mesangial cells might inhibit cAMP through

a membrane-delimited pathway that requires activation

of Gi/o-proteins.


3.1.4. 5-hydroxytryptamine2A receptor activates the

extracellular signal-regulated mitogen-activated

protein kinase

Several groups have documented that the 5-HT2A

receptor activates ERK MAP kinases in cells with con-

tractile phenotypes, vascular smooth muscle cells (Florian

& Watts, 1998; Watts, 1998) and renal mesangial cells

(Grewal et al., 1999; Greene et al., 2000). In vascular

smooth muscle cells, the activation of ERK was complex,

requiring inputs from PLC, L-type Ca2 + channels, and

MEK1 (Florian & Watts, 1998; Watts, 1998). In mesangial

cells, the pathway also involves stimulation of PKC,

activation of an NAD(P)H oxidase-like enzyme, and pro-

duction of reactive oxygen species (H2O2 and/or super-

oxide) (Grewal et al., 1999; Greene et al., 2000). The

activation of ERK in vascular smooth muscle cells is in-

volved in contraction, whereas the activation in mesangial

cells results in proliferation (Takuwa et al., 1989); induction

of early response genes, such as Egr-1 and cyclo-oxygenase-

2 (Goppelt-Struebe & Stroebel, 1998); and up-regulation of

the matrix-regulatory cytokine, TGF-b (Grewal et al., 1999).In contrast, ERK does not appear to be involved in the up-

regulation of another of the matrix-regulatory cytokines

(connective tissue growth factor) by the 5-HT2A receptor

in mesangial cells. Rather, a small G-protein (Rho) and the

actin cytoskeleton appear to mediate the up-regulation

(Hahn et al., 2000).

3.1.5. The 5-hydroxytryptamine2A receptor activates the

Janus kinase/signal transducers and activators of

transcription pathway

Guillet-Deniau et al. (1997) identified a 5-HT2A receptor

in rat skeletal muscle myoblasts that is coupled to the Janus

kinase (Jak)/signal transducers and activators of transcrip-

tion (STAT) pathway. The receptor was detected on the

plasma membrane and in T-tubules in contracting myo-

tubes. It was shown to increase the expression of genes

involved in myogenic differentiation, and to trigger a

rapid tyrosine phosphorylation of Jak2 and STAT3, result-

ing in translocation into the nucleus of STAT3. The

5-HT2A receptor co-precipitated with Jak2 and STAT3,

indicating that they are physically associated (Guillet-

Deniau et al., 1997).

3.1.6. The 5-hydroxytryptamine2A receptor

regulates apoptosis

Increasing levels of 5-HT in the cerebral cortex coincide

with developmental events, such as cell proliferation, sur-

vival, and differentiation. Dooley et al. (1997) used a cell-

survival assay to show that stimulation of the 5-HT2A

receptor promoted the survival of rat cortical progenitor cells

in vitro. They further demonstrated that this effect was

specific to the glutamate-containing post-mitotic neuron

population, and not to dividing neuroepithelial cells in the

developing cortex (Dooley et al., 1997).


regulates channels

The 5-HT2A receptor increases intracellular Ca2 + levels

by liberating intracellular stores of Ca2 + and/or by activ-

ating Ca2 + channels, depending upon the cell of interest.

The 5-HT2A receptor may activate L-type Ca2 + channels in

some cell types (Eberle-Wang et al., 1994; Jalonen et al.,

1997; Watts, 1998). Although because of significant overlap

in the pharmacology of the L-type Ca2 + channels and the

5-HT2A receptor antagonists (Okoro, 1999), one should

proceed with prudence before attributing effects of the

5-HT2A receptor to L-type Ca2 + channels. The Ca2 + channels

coupled to the 5-HT2A receptor have been characterized as

both voltage-dependent and -independent (Nakaki et al.,

1985; Eberle-Wang et al., 1994; Hagberg et al., 1998). The

increases in Ca2 + levels evoked by the 5-HT2A receptor

have been linked to subsequent opening of Ca2 + -activated

K + channels in C6 glial cells (Bartrup & Newberry, 1994)

and to an inward current mediated through Ca2 + -activated

Cl- channels in Xenopus oocytes (Montiel et al., 1997).

In rat cortical astrocytes, the 5-HT2A receptor activates

both an L-type Ca2 + channel and an apamin-sensitive

Ca2 + -activated small conductance K + channel (Jalonen

et al., 1997).

3.1.8. The 5-hydroxytryptamine2A receptor causes

production of reactive oxygen and nitrogen species

Preliminary reports suggest that the 5-HT2A receptor can

either stimulate or inhibit NO synthesis in certain tissues and

cells. For example, gastrointestinal transit is regulated by

5-HT2A receptor-induced release of NO (Matsuda et al.,

2000). On the other hand, 5-HT2A receptors also inhibit

cytokine-stimulated inducible NOS in C6 glioma cells

(Miller & Gonzalez, 1998).

The 5-HT2A receptor in renal mesangial cells has been

shown to induce the production of H2O2 and superoxide

through the action of an NAD(P)H oxidase-like enzyme

(Grewal et al., 1999). The enzyme resides downstream from

PKC, and is an important upstream activator of ERK by the

5-HT2A receptor in those cells (Greene et al., 2000).


regulates calmodulin

It is not surprising that CaM should be a target for 5-HT2

receptor signaling, in that CaM is a major signaling target

of Ca2 + mobilization in most cells types. There are three lines

of indirect evidence that the 5-HT2A receptor signals through

CaM. First, agonist-mediated up-regulation of the 5-HT2A

receptor depends upon CaM and Ca2 +/CaM-dependent

kinase 2 (Chen et al., 1995). Second, Berg et al. (1994a)

showed that the 5-HT2A receptor increases cAMP formation

in A1A1 cells by the intermediate action of CaM. Third,

inhibition of CaM-dependent kinase 2 or calcineurin (a CaM-

dependent phosphatase) inhibits 5-HT-induced cyclo-oxy-

genase 2mRNA expression in renal mesangial cells (Stroebel

& Goppelt-Struebe, 1994; Goppelt-Struebe et al., 1999).



transport processes

Like the 5-HT1A receptor (see Section 2.1.11), the 5-HT2A

receptor has been linked to a variety of transport processes. It

activates the Type 1 Na + -proton exchanger in renal mesan-

gial cells (Saxena et al., 1993; Garnovskaya et al., 1995). The

5-HT2A receptor in airway smooth muscle stimulates the

Na + /K + -ATPase (Na + pump) through a pathway that might

involve activation of the Na + -proton exchange exchanger

(Rhoden et al., 2000). In contrast, 5-HT2A receptor trans-

fected into NIH 3T3 fibroblasts was unable to stimulate Na +

pump activity; rather, it activated Na + /K + /2Cl- cotransport

(Mayer & Sanders-Bush, 1994).

The 5-HT2A receptor expressed endogenously in rat renal

mesangial cells accelerates mediator-facilitated electron

fluxes across the plasma membrane through a process that

may be linked to the production of reactive oxygen species

(Grewal et al., 1999). The 5-HT2A receptor enhances release

of dopamine and norepinephrine, but not 5-HT, in the frontal

cortex of freely moving rats (Gobert & Millan, 1999). Both

5-HT2A and 5-HT2C receptors stimulate amyloid precursor

protein ectodomain secretion through a pathway that in-

volves PLA2 (Nitsch et al., 1996).

3.1.11. A unique signaling role for internalization of the

5-hydroxytryptamine2A receptor

The 5-HT2A receptor is internalized in response to both

agonists and antagonists, adding a very interesting twist to its

signaling properties (Bhatnagar et al., 2000). This feature of

the 5-HT2A receptor may play important roles in its signaling

and in the actions of antipsychotic medications. Bhatnagar

et al. (2000) examined the internalization process of this

receptor in detail, demonstrating that both agonist- and

antagonist-induced internalization of the 5-HT2A receptor

were dynamin-dependent. In contrast, both agonist- and

antagonist-induced internalizations of a 5-HT2A receptor-

green fluorescent protein fusion protein were insensitive to

three different dominant-negative mutants of arrestin.

Activation of the 5-HT2A receptor by agonists, but not anta-

gonists, induced greater translocation of arrestin-3 than

arrestin-2 to the plasma membrane, and resulted in differ-

ential sorting of arrestin-2, arrestin-3, and 5-HT2A receptors

into distinct plasma membrane and intracellular compart-

ments. It is likely that these differences in distribution of the

various signaling components induced by agonists and

antagonists may be important in the ‘‘ligand-directed’’ of

second messenger signals by the 5-HT2A receptor, depend-

ing upon which ligand is used to stimulate the receptor.

3.2. The 5-hydroxytryptamine2B receptor

The 5-HT2B receptor was first described as the receptor

that mediates contraction of the gastric fundus (Vane, 1959).

The receptor was cloned from rat and mouse in 1992

(Foguet et al., 1992a, 1992b) and from human in 1994

(Kursar et al., 1994). The receptor was formerly termed

either 5-HT2F (Wainscott et al., 1993) or SRL (Foguet et al.,

1992b). The human receptor protein is 481 amino acids in

length (Kursar et al., 1994), and it has 2 introns similar to

the 5-HT2A and 5-HT2C receptors. The human receptor has

45% homology with the 5-HT2A receptor and 42% homol-

ogy with the 5-HT2C receptor (Barnes & Sharp, 1999). The

human 5-HT2B receptor gene is localized to chromosome

2q36.3-2q37.1.

mRNA encoding the 5-HT2B receptor is expressed with

greatest abundance in the human liver and kidney. Lower

levels of expression have been detected in the pancreas and

spleen (Bonhaus et al., 1995), but the presence of mRNA for

the 5-HT2B receptor in the brain appears to be relatively

limited (Loric et al., 1992; Kursar et al., 1994). 5-HT2B

receptor immunoreactivity has been reported in neurons in

the cerebellum, dorsal hypothalamus, lateral septum, and

medial amygdala (Duxon et al., 1997).

3.2.1. The 5-hydroxytryptamine2B receptor activates

phospholipase C

Like the 5-HT2A and 5-HT2C receptors, the 5-HT2B

receptor couples consistently to PLC. The cloned rat and

human receptors stimulate inositol phosphate accumulation

when expressed heterologously in mammalian cells (Wain-

scott et al., 1993; Kursar et al., 1994; Schmuck et al., 1994;

Kellermann et al., 1998) or endogenously in IC11 cells (Loric

et al., 1995). The 5-HT2B receptor also has been reported to

stimulate Ca2 + mobilization in astrocytes derived from rat

cerebral cortex, hippocampus, and brain stem (Sanden et al.,

2000). The 5-HT2A and 5-HT2C receptors can activate other

PLs, but there is less evidence that the 5-HT2B receptor can

do so. The 5-HT2B receptor has been shown in one report to

activate PLA2 in IC11 cells (Tournois et al., 1998). However,

the 5-HT2B does not couple to PLD in the rat stomach fundus

(Cox et al., 1999).

3.2.2. The 5-hydroxytryptamine2B receptor can stimulate

cyclic amp accumulation

The 5-HT2B receptor does not typically regulate cAMP

production, but when heterologously expressed in AV12

cells, it induces a modest increase in cAMP levels (Lucaites

et al., 1996).


morphogenesis and mitogenesis

Choi et al. (1997) reported that 5-HT2B receptors regulate

embryonic morphogenesis, probably by preventing the dif-

ferentiation of cranial neural crest cells and myocardial

precursor cells. Their evidence was that 5-HT2B receptor

antagonists had specific effects on embryonic cultures, such

that they induced morphological defects in the cephalic

region, heart, and neural tube. 5-HT2B receptor antagonists

interfered with cranial neural crest cell migration and induced

their apoptosis. In the heart, antagonists caused abnormal

sarcomeric organization in the subepicardium and induced

the specific absence of the trabecular cell layer in the


ventricular myocardium. The specific signaling pathways

involved in the regulation of cellular migration, apoptosis,

and morphogenesis remain to be defined, but a study by

Nebigil et al. (2000a) suggests that ErbB-2might be involved.

Nebigil et al. (2000a) generated 5-HT2B receptor knock-

out mice, which resulted in embryonic and neonatal death

caused by specific heart defects. The knockout embryos

lacked trabeculae in the heart, leading to midgestation

lethality. Surviving newborn mice displayed a severe

ventricular hypoplasia associated with impaired prolifera-

tive capacity of myocytes. In surviving adult knockout

mice, there were severe cardiac histopathological changes,

including myocyte disarray and ventricular dilation. They

also found that there was a specific reduction in the

expression levels of the receptor tyrosine kinase ErbB-2.

Their data suggest that the 5-HT2B receptor probably

requires ErbB-2 in the signaling pathway for cardiac

differentiation (Nebigil et al., 2000a).

3.2.4. The 5-hydroxytryptamine2B receptor activates

the extracellular signal-regulated kinase and cell

cycle components

Launay et al. (1996) showed that 5-HT2B receptors stably

expressed in mouse fibroblast LMTK- cells rapidly activate

the proto-oncogene Ras and ERK1/ERK2 MAP kinases.

This pathway also involves Gaq and Gbg. This pathway also

stimulated 5-HT-dependent proliferation of the transfected

cells. The 5-HT2B receptor expressed in LMTK- cells can

induce foci formation, and when injected into nude mice,

the foci cause tumors (Launay et al., 1996). This effect is

mediated through the Ras-ERK pathway.

Nebigil et al. (2000b) presented evidence that the

5-HT2B receptor can stimulate cell cycle progression

through an ERK-dependent pathway. The pathway also

leads to hyperphosphorylation of Rb through up-regulation

and activation of both cyclin D1/cdk4 and cyclin E/cdk2

kinases. The pathway leading to up-regulation and activa-

tion of ERK and cyclin D1, but not cyclin E, requires the

intermediate activation of the platelet-derived growth factor

(PDGF) receptor kinase signaling pathways. Moreover,

activation of the PDGF receptor, activation of ERK, up-

regulation and activation of both cyclin D1 and cyclin E,

and cellular proliferation all depend upon the non-receptor

tyrosine kinase Src (Nebigil et al., 2000b). Thus, the

5-HT2B receptor stimulates cellular proliferation through

two parallel pathways. These are as follows: (1) 5-HT2B

receptor ! Gq ! Src ! PDGF receptor tyrosine

kinase ! ERK ! cyclin D1/cdk4 ! Rb hyperphos-

phorylation ! proliferation and (2) 5-HT2B receptor !Gq ! Src ! ? ! cyclin E/cdk2 ! Rb hyperphos-

phorylation ! proliferation.

3.2.5. The 5-hydroxytryptamine2B receptorcauses production

of reactive nitrogen species

The 5-HT2B receptor increases production of NO in

human coronary artery endothelial cells (Ishida et al., 1998)

and in porcine cerebral artery, where this results in vaso-

relaxation (Florian & Watts, 1998). In contrast, a role for NO

in 5-HT2B receptor-mediated contraction of the stomach

fundus has been challenged (Cox & Cohen, 1995). Manivet

et al. (2000) published an elegant study in which they

documented that 5-HT2B receptors expressed endogenously

in IC11 cells and Mastomys natalensis carcinoid cells or

expressed heterologously in LMTK- fibroblasts stimulate

intracellular cGMP production through dual activation of

constitutive NOS (cNOS) and inducible NOS (iNOS). This

coupling relied on the Group I PDZ motif in the carboxyl

terminal tail of the 5-HT2B receptor, a conclusion based on

competition with a carboxyl terminal fragment of the receptor

and upon studies in which a mutant receptor lacking the PDZ

interaction motif could not couple to cNOS or iNOS (Man-

ivet et al., 2000). Neutralizing antibodies raised against Ga13

blocked activation of iNOS, but not cNOS, activity. Thus, the

5-HT2B receptor can activate NO production through two

overlapping pathways: (1) 5-HT2B receptor ! PDZ inter-

action motif + Ga13 ! iNOS ! NO/cGMP and 5-HT2B

receptor ! PDZ interaction motif ! cNOS ! NO/cGMP

(Manivet et al., 2000). Thus, the ability of the 5-HT2B

receptor to increase NO levels depends upon interactions

with two isoforms of NOS.

3.2.6. The 5-hydroxytryptamine2B receptor

regulates channels

The 5-HT2B receptor induces release of Ca2 + from ryano-

dine-sensitive intracellular stores in human pulmonary artery

endothelial cells through a pathway that involves activation

of ryanodine receptors, but is independent of accumulation

of inositol phosphates (Ullmer et al., 1996). In contrast,

in Xenopus oocytes, the 5-HT2B receptor activates Ca2 +

oscillations through a pathway that involves IP3-dependent

release of internal Ca2 + stores, as well as Ca2 + influx. The

increased Ca2 + leads to activation of a Ca2 +-dependent Cl-

channel (Foguet et al., 1992a; Parekh et al., 1993).


transport processes

Leung et al. (1999) used the short-circuit current tech-

nique to demonstrate that the 5-HT2B receptor can stimulate

bicarbonate secretion through a process that is dependent

upon prostaglandin synthesis in cultured rat epididymal

epithelium. The 5-HT2B receptor may be able to regulate

other transport processes, in that it has been reported to

stimulate phosphorylation of the 5-HT transporter SERT and

of the Na +/K +-ATPase (Launay et al., 1998).

3.3. The 5-hydroxytryptamine2C receptor

The 5-HT2C receptor (originally called the 5-HT1C recep-

tor) was identified as a high-affinity [3H]5-HT-binding site in

the choroid plexus (Pazos et al., 1985). The cloning of mouse

(Lubbert et al., 1987; Yu et al., 1991), rat (Julius et al., 1988),

and human (Saltzman et al., 1991) 5-HT2C receptors led to the


recognition that the 5-HT2C receptor is much more closely

related to the 5-HT2 receptor family than to the 5-HT1

receptor family. The receptor gene is located on chromosome

Xq24, and contains three introns (Yu et al., 1991; Stam et al.,

1994; Xie et al., 1996). A nonfunctional truncated splice

variant of the 5-HT2C receptor has been reported (Canton

et al., 1996; Xie et al., 1996). To date, no other splice

variants of the 5-HT2C receptor have been identified. How-

ever, the 5-HT2C receptor exhibits a very unique mechanism

of generating multiple functional receptor variants through a

process called mRNA editing (Burns et al., 1997). This

unique feature will be discussed in Section 3.3.8.

The 5-HT2C receptor is expressed nearly exclusively in

the brain. High levels of 5-HT2C receptor expression have

been detected by ligand autoradiography, immunocyto-

chemistry, and in situ hybridization in the choroid plexus,

the cortex, the nucleus accumbens, the amygdala, the

hippocampus caudate nucleus, and the substantia nigra

(Pazos et al., 1985; Mengod et al., 1990; Palacios et al.,

1990; Abramowski et al., 1995).

3.3.1. The 5-hydroxytryptamine2C receptor activates

phospholipase C

The 5-HT2C receptor has long been recognized as being

capable of activating PLC in the choroid plexus (Sanders-

Bush et al., 1988) and other brain regions (Wolf & Schutz,

1997). A major signal transduction cascade linked to the

5-HT2C receptor in transfected cells is also stimulation of

PLC-mediated inositol phosphate accumulation (Julius et al.,

1988; Berg et al., 1994b, 1998; Briddon et al., 1998;

Grotewiel & Sanders-Bush, 1999), although it can activate

PLA2-mediated AA release as well (Berg et al., 1996,

1998). The activation of PLC probably is mediated through

Gq/11a-proteins, although Chen et al. (1994) presented evid-

ence that the 5-HT2C receptor could couple to Goa and Gia1 in

Xenopus oocytes. Chang et al. (2000) used an elegant method

of delivering membrane-permeable blocking peptides to

document that 5-HT2C receptors expressed in the choroid

plexus activate PLC through Gqa-proteins and not through

bg-subunits. In their study, peptide mimics of Gqa and the

Gqa interaction domain of PLCb1 prevented 5-HT2C recep-

tor-mediated accumulation of inositol phosphates, whereas

peptides derived from bg-binding sites of PLCb2 and a

phosducin-like protein C-terminus did not. The latter two

peptides were quite effective in blocking the Gbg-mediated

activation of ERK by the a2A-adrenergic receptor. Tohda

et al. (1995) also suggested that botulin toxin-sensitive, low-

molecular weight G-proteins are important in the inositol

phosphate accumulation induced by the 5-HT2C receptor in

COS-7 cells.

Like the 5-HT2A and 5-HT2B receptors, the 5-HT2C

receptor can also activate PLA2, but the story for the

5-HT2C receptor has an intriguing twist. Berg and colleagues

(1998) compared the ability of a panel of agonists to activate

both PLA2 and PLC in cells expressing transfected 5-HT2A

and 5-HT2C receptors. They showed that for the 5-HT2C

receptor, some agonists preferentially activated PLA2 or

PLC, when relative efficacies were referenced to 5-HT. This

is probably the best evidence for ‘‘agonist-directed traffick-

ing of receptor stimulus,’’ meaning that a single receptor

subtype can couple with different efficacies to several signal-

ing pathways, depending upon the nature of the agonist to

which the receptor is exposed. In contrast, the results for the

5-HT2A receptor showed that all agonists demonstrated

greater relative efficacies for PLA2 than for PLC.

3.3.2. The 5-hydroxytryptamine2C receptor can modulate

cyclic AMP accumulation

When expressed at physiological levels, the 5-HT2C

receptor has not been reported to modulate cAMP levels

in cells or tissues. When expressed at high density

(12 pmol/mg membrane protein) in stably transformed

AV12 cells, however, the 5-HT2C receptor has been shown

to inhibit forskolin-stimulated cAMP production, with an

IC50 of � 50 nM. This effect was sensitive to pertussis

toxin, suggesting the involvement of Gi/o-proteins. In

contrast, the 5-HT2A and 5-HT2B receptors expressed at

similar levels did not decrease AC activity in those cells.

Pretreatment of the cells expressing high levels of 5-HT2C

receptor with pertussis toxin also unmasked a small

stimulatory effect of the 5-HT2C receptor on cAMP accu-

mulation. When expressed at low density, the 5-HT2C

receptor could potentiate forskolin-stimulated cAMP pro-

duction by � 2-fold (Lucaites et al., 1996).

3.3.3. The 5-hydroxytryptamine2C receptor

regulates channels

The 5-HT2C receptor can regulate K + and Cl- channels.

The cloned 5-HT2C receptor has been shown to close K +

channels in the choroid plexus (Hung et al., 1993) and when

expressed in cell lines (Kelly et al., 1991; Panicker et al.,

1991). DiMagno et al. (1996) showed that the 5-HT2C

receptor, when co-expressed in Xenopus oocytes with rat

brain mRNA, could inhibit an inwardly rectified, Ba2 +-

sensitive K + conductance through a PKC-dependent path-

way. When co-expressed in Xenopus oocytes, the 5-HT2C

receptor also suppresses the activity of the Shaker-related

K + gene Kv1.3, which encodes the type n K + channel. This

effect on Kv1.3 currents proceeds via activation of a per-

tussis toxin-sensitive G-protein and a subsequent rise in

intracellular Ca2 + , but not via PKC, Ca2 + /CaM or phos-

phatases (Aiyar et al., 1993). Timpe and Fantl (1994) used a

similar system to show that the 5-HT2C receptor suppressed

the activity of the voltage-activated K + channel Kv1.5

through a PLC-dependent pathway.

The 5-HT2C receptor has also been shown to stimulate an

apical Cl- conductance in mouse choroid plexus (Hung

et al., 1993). 5-HT2C receptors have been shown to inhibit

g-aminobutyric acid (GABA)-A receptor channels by a

Ca2 + -dependent, phosphorylation-independent mechanism

in Xenopus oocytes (Huidobro-Toro et al., 1996). 5-HT2C

receptors expressed in Xenopus oocytes can stimulate Ca2 +


release from IP3-sensitive intracellular stores, which results

in the opening of Ca2 + -gated Cl- channels (Walter et al.,

1991; DiMagno et al., 1996). This effect occurs through

endogenous Go-proteins in Xenopus oocytes. The same Cl-

current could also be stimulated by co-expression of four

isoforms of mammalian G-protein a-subunits (Goa, Gob,

Gqa, G11a), along with the 5-HT2C receptor. The effect was

mediated by a PLC-b endogenous to the Xenopus oocytes.

The same assay failed to detect any modulation of cAMP or

of three G-proteins (Gta, Golfb, Gsa, G11a) by the 5-HT2C

receptor (Quick et al., 1994). The physiological significance

of these effects is not known.

3.3.4. The 5-hydroxytryptamine2C receptors

regulate mitogenesis

The recombinant 5-HT2C receptor, when expressed in

NIH 3T3 cells, results in the generation of transformed

foci. Moreover, the injection of cells derived from trans-

formed foci into nude mice has been shown to result in the

generation of tumors (Julius et al., 1989). However, when

expressed in CCL36 fibroblasts, the 5-HT2C receptor

mediates only a very weak transforming activity (Kahan

et al., 1992).

3.3.5. The 5-hydroxytryptamine2C receptor can regulate

nitric oxide levels

The 5-HT2C receptor has been shown to both inhibit and

stimulate production of NO. It inhibits NMDA-induced

cGMP production and increases NO in rat cerebellum

(Marcoli et al., 1997) and in human neocortical slices

(Maura et al., 2000). In contrast, the 5-HT2C receptor can

stimulate cGMP and NO production in the choroid plexus

through a pathway that requires Ca2 + , PLA2, and lipox-

ygenase activity (Kaufman et al., 1995).

3.3.6. The 5-hydroxytryptamine2C receptor regulates

transport processes

The 5-HT2C receptor has been shown to modulate a

number of distinct transport processes. Recombinant

5-HT2C receptors expressed in 3T3 cells can activate pro-

cessing of amyloid precursor proteins. This process involves

both PKC and PLA2 (Nitsch et al., 1996).

The 5-HT2C receptor activates an electrogenic Na + /

Ca2 + exchanger in histaminergic neurons in the rat hypo-

thalamic tuberomammillary nucleus. This results in a doub-

ling of the firing rates of the neurons and depolarization

(Eriksson et al., 2001). The 5-HT2C receptor might also

stimulate prolactin (Cowen, P. J. et al., 1996), corticoster-

one, and ACTH secretion (Fuller, 1996), and inhibit the

neuronal release of norepinephrine and dopamine, but not

5-HT (Millan et al., 1998).

3.3.7. Possible signaling through PS-95 discs-large ZO-1

interaction motifs by the 5-hydroxytryptamine2C receptor

The 5-HT2C receptor has been shown in a yeast two-

hybrid screen to interact with a novel multivalent PDZ

protein called MUPP1. The C-terminus of the 5-HT2C

receptor selectively interacts with the tenth PDZ domain

of MUPP1. Both proteins were shown to interact by con-

focal microscopy and by co-immunoprecipitation studies in

COS-7 cells. Thus, Becamel et al. (2001) proposed that

MUPP1 might function as a multivalent scaffold protein,

which selectively assembles and targets 5-HT2C receptor-

signaling complexes. The interaction between MUPP1 and

the 5-HT2C receptor is functionally significant in two

regards. First, the interaction leads to a conformational

change in MUPP1 (Becamel et al., 2001). Second, deletion

of the 5-HT2C receptor PDZ recognition motif prevents

phosphorylation of the receptor and delays resensitization

of receptor responses (Backstrom et al., 2000). These

findings open up an exciting new area of GPCR signaling

that may function independently from, or in concert with,

G-protein-dependent pathways.

3.3.8. Multiple novel functional 5-hydroxytryptamine2Creceptors are created by mRNA editing

The 5-HT2C receptor exhibits a very unique mechanism

of generating multiple functional receptor variants through

a process called mRNA editing (Burns et al., 1997).

Niswender et al. (1998) examined the possibility that the

5-HT2A and 5-HT2B receptors might also undergo RNA

editing in the i2 loop using a polymerase chain reaction

strategy, but were unable to show any evidence that this

process occurs for those receptors. They also noted that five

genomically encoded adenosines within the putative i2 loop

of the 5-HT2C receptor were converted to guanosines at the

RNA level. These sites are referred to as sites A–E. The

editing of the mRNA probably occurs by de-amidation of

the adenosines to inosines, which are read at the RNA level

as guanosines. In the human 5-HT2C receptor, various

combinations of A ! G conversions result in at least 21

discrete mRNA species encoding 14 different editing var-

iants of the 5-HT2C receptor. The genomic (unedited)

receptor expresses amino acids INI (in the sequence IRNPI

in i2), whereas conversion of all three amino acids results in

VNV, VSV, VGV, or VDV (Niswender et al., 1998; Back-

strom et al., 1999; Fitzgerald et al., 1999). These are referred

to as 5-HT2C-INI, 5-HT2C-VNV, 5-HT2C-VSV, 5-HT2C-VGV, and

5-HT2C-VDV receptors. Other human receptor variants are

5-HT2C-VNI, 5-HT2C-VSI, 5-HT2C-ISI, 5-HT2C-INV, 5-HT2C-ISV,

5-HT2C-IGI, 5-HT2C-VGI, 5-HT2C-IDI, and 5-HT2C-IDV recep-

tors. The situation in rats is not identical, in that only 4 A

! G conversion sites (termed sites A–D) have been

identified, resulting in 11 discrete mRNAs and 7 different

receptor protein isoforms (Fitzgerald et al., 1999; Niswender

et al., 1999).

The functional significance of the various edited iso-

forms of the 5-HT2C receptor is underscored by their

differential abundances of expression in total brain and

hypothalamic mRNA populations (Fitzgerald et al., 1999).

Moreover, the variant edited receptors exhibit differential

abilities to bind various ligands, to mobilize intracellular


Ca2 + , and to stimulate accumulation of inositol phosphates

(Niswender et al., 1998; Backstrom et al., 1999; Fitzgerald

et al., 1999).

4. The 5-hydroxytryptamine4 receptor

Three types of 5-HT receptors couple primarily to the

activation of AC: the Gs-coupled 5-HT4, 5-HT6, and 5-HT7

receptors (Hamblin et al., 1998). Unlike the 5-HT6 and

5-HT7 receptors, the 5-HT4 receptor was well-characterized

pharmacologically and functionally (Dumuis et al., 1988;

Bockaert et al., 1990) prior to its cloning. The major

functional effects of the 5-HT4 receptors are prokinetic

actions in the gut and positive inotropy, chronotropy, and

lusitropy in atria, but not ventricles (Kaumann, 1991).

The human 5-HT4 gene is thought to be highly complex,

with multiple introns (Bockaert et al., 1998b). It maps to

chromosome 5q31-q33 (Claeysen et al., 1997). In 1995,

Gerald et al. reported the isolation of two rat brain 5-HT4

receptors. These were originally termed 5-HT4S and 5-HT4L

to indicate that they are short (387 amino acids) and long

versions (406 amino acids) of the 5-HT4 receptor (Gerald

et al., 1995). Similar murine cDNA homologues of these

receptors were subsequently reported (Claeysen et al.,

1996), and these were proposed to be renamed 5-HT4a

and 5-HT4b receptors, to be more in keeping with the

recommendations of the Nomenclature Committee of the

International Union of Pharmacology (Hoyer et al., 1994).

Two later reports suggested that the correct length of the

longer isoform (5-HT4b receptor) is actually 388 amino

acids (Van den Wyngaert et al., 1997; Bockaert et al.,

1998b). The putative protein products share sequence iden-

tity from amino acids 1–358, and diverge in amino acid

sequence after L358. Subsequently, four other splice variants

of this receptor have been shown to differ only in the length of

their intracellular carboxyl terminal tails. The human 5-HT4c

and 5-HT4d receptors are 380 and 360 amino acids in length,

respectively (Blondel et al., 1998; Claeysen et al., 1998). The

human 5-HT4e receptor is 378 amino acids in length (Claey-

sen et al., 1999). The corresponding rodent 5-HT4e receptor is

371 amino acids in length. The 5-HT4f receptor has been

identified in the mouse and is 363 amino acids in length; a

human 5-HT4f receptor has not been identified yet (Claeysen

et al., 1999).

There may be subtle differences in the distribution of

5-HT4a and 5-HT4b receptor splice variants (Shen et al.,

1993; Blondel et al., 1997), although this has not been a

universal finding (Claeysen et al., 1996; Vilaro et al., 1996).

5-HT4a, 5-HT4b, and 5-HT4c receptors are expressed in the

brain, the atrium, and the gut, whereas the 5-HT4d receptor

has only been detected in the gut (Blondel et al., 1998). The

human 5-HT4d receptor is localized in the atrium and the

brain, but not in the gut (Mialet et al., 2000), whereas mouse

and rat 5-HT4d receptors and mouse 5-HT4e and 5-HT4f

receptors are brain-specific (Claeysen et al., 1999).

4.1. The 5-hydroxytryptamine4 receptor activates

adenylyl cyclase

The 5-HT4 receptors prototypically stimulate AC when

expressed endogenously in tissues (Dumuis et al., 1988;

Bockaert et al., 1990; Ford et al., 1992; Albuquerque

et al., 1998; Bach et al., 2001) or heterologously in cells

(Gerald et al., 1995; Blondel et al., 1998; Bockaert et al.,

1998b; Claeysen et al., 1998; Mialet et al., 2000). When

transiently expressed in COS-7 cells, four splice variants

of the 5-HT4 receptor displayed similar abilities to

stimulate AC activity in the presence of 5-HT (Blondel

et al., 1998).

4.2. The 5-hydroxytryptamine4 receptor activates protein

kinase A

As would be expected for receptors whose primary

effect is to increase cAMP levels, most of the effects of

the 5-HT4 receptors are due to activation of PKA. These

include positive inotropic, chronotropic, and lusitropic

effects in the atria (Kaumann, 1991); inhibition of a K +

current in colliculi neurons (Fagni et al., 1992); facilitation

of striatal dopamine release (Steward et al., 1996); relaxa-

tion of the circular smooth muscle of the human colon

(McLean & Coupar, 1996); and regulation of the Ca2 + -

activated K + current in adult hippocampal neurons (Torres

et al., 1995).

4.3. The 5-hydroxytryptamine4 receptor regulates channels

5-HT4 receptors can regulate a variety of channels. For

example, activation of L-type Ca2 + channels (Kaumann,

1991; Ouadid et al., 1992) is probably responsible for the

prokinetic actions of the 5-HT4 receptors in the gut and

positive inotropy in the heart by activating cardiac L-type

Ca2 + channels. In human atrial myocytes, activation of

L-type Ca2 + channels by the 5-HT4 receptor occurs via an

elevation of intracellular cAMP levels and stimulation of

PKA (Ouadid et al., 1992). The 5-HT4 receptor increases the

If pacemaker current in atrial myocytes (Pino et al., 1998)

and stimulates a Cl- current in human jejunal mucosa and

rat distal colon (Budhoo et al., 1996a, 1996b). The 5-HT4

receptor stimulates a tetrodotoxin-insensitive Na + current

in Type II dorsal root ganglion cells through a diffusible

second messenger pathway that does not appear to involve

cAMP (Fagni et al., 1992). Thus, this receptor may modulate

channel function through pathways other than the cAMP/

PKA pathway.

The 5-HT4 receptor does not universally stimulate

channels, in that it inhibits a Ca2 + -activated K + current

responsible for the slow afterhyperpolarization in adult

hippocampal neurons (Andrade & Chaput, 1991). This

effect is mediated by increased cAMP and activation of

PKA (Torres et al., 1995). Ansanay et al. (1995) showed

that the 5-HT4 receptor induces long-lasting inhibition of


a K + current in murine colliculi neurons through a PKA

and phosphatase-regulated pathway. 5-HT4 receptors also

inhibit (long-lasting) a delayed rectifier voltage-dependent

K + current similar to KV3.2 (Bockaert et al., 1998a).

The 5-HT4 receptor in mouse colliculi neurons inhibits a

voltage-activated K + current through cAMP and PKA

(Fagni et al., 1992).

4.4. The 5-hydroxytryptamine4 receptor regulates transport

5-HT stimulates aldosterone secretion in humans through

5-HT4 receptors positively coupled to AC (Lefebvre et al.,

1997, 2000). 5-HT4 receptors also facilitate rat striatal dop-

amine release in vitro and in vivo (Steward et al., 1996),

release of acetylcholine from rat frontal cortex (Consolo et al.,

1994), and release of 5-HT from rat hippocampus (Ge &

Barnes, 1996).

4.5. Functional differences among the 5-hydroxytryptamine4receptor splice variants

Although four splice variants of the 5-HT4 receptor, when

transiently expressed in COS-7 cells, were reported to

display similar abilities to stimulate AC activity in the

presence of 5-HT (Blondel et al., 1998), some interesting

differences in the behavior of the splice variants have been

observed (Claeysen et al., 1999). The 5-HT4e and 5-HT4f

receptors induce significantly more agonist-independent

increases in AC activity than do longer isoforms of the

5-HT4 receptor splice variants. The authors presented data

in support of a model in which a serine-threonine rich

portion of the carboxyl terminus of the receptor that is

shared by all of the splice variants (residues 346–359) holds

the receptor in an inactive conformation. Longer splice

variants, such as 5-HT4a and 5-HT4b receptors, augment

the inhibitory function of residues 346–359, whereas

shorter splice variants, such as the 5-HT4e and 5-HT4f

receptors, do not, resulting in increased basal cAMP levels

(Claeysen et al., 1999). An alternative interpretation of their

data is that the carboxyl terminus may be involved in rapid

or constitutive desensitization. Thus, removal of the carbox-

ylterminus could increase basal activity by reducing con-

stitutive desensitization. Evidence for this mechanism has

been presented recently for the B2 bradykinin receptor

(Leeb-Lundberg et al., 2001). This fascinating story is likely

to become more interesting, as the 5-HT4b receptor splice

variants differ in their expression of distinct PDZ interaction

motifs (Hamblin et al., 1998; Claeysen et al., 1999), which

may alter their signaling properties.


Currently, little is known about 5-ht5 receptors. As func-

tional 5-ht5 receptors have not been identified in vivo yet, the

lower case designation is used. Cloning experiments have

revealed two subtypes of the 5-ht5 receptor, termed 5-ht5a and

5-ht5b. Both 5-ht5a and 5-ht5b receptors have been cloned

from rat and mouse, but only the 5-ht5a receptor has been

cloned from human (Plassat et al., 1992; Erlander et al., 1993;

Matthes et al., 1993; Wisden et al., 1993; Rees et al., 1994).

The human 5-ht5A receptor gene encodes a protein of 357

amino acid residues, has a single intron, and is located on

chromosome 7q36 (Rees et al., 1994). The human 5-ht5breceptor cDNA and its gene have not been cloned yet, but the

gene is localized to chromosome 2q11-13 (Matthes et al.,

1993). The rodent 5-ht5b receptor genes contain a single

intron in the middle of the putative i3 loops, and they encode

proteins of 370 or 371 amino acids.

The 5-ht5 receptors have high affinity for lysergic acid

diethylamide (LSD) and 5-carboxamidotryptamine. Both

receptors are expressed in multiple brain regions, but not

in peripheral tissues (Plassat et al., 1992; Rees et al., 1994).

Waeber and Moskowitz (1995) were able to identify putat-

ive 5-ht5a receptors by comparative autoradiography with

[3H]5-carboxamidotryptamine and [125I]LSD in wild-type

and 5-ht5a receptor knockout mice. Studies with [3H]5-

carboxamidotryptamine (in the presence of 8-OH-DPAT,

GR127935, and spiperone) revealed no binding in knockout

mice, but intermediate levels of binding in wild-type mice in

the olfactory bulb and neocortex. This binding probably

represents the 5-ht5a receptor. They also observed high

densities of [125I]LSD binding (in the presence of clozapine

and spiperone) in the medial habenula of wild-type and

knockout mice. However, 5-carboxamidotryptamine com-

peted for [125I]LSD binding with an affinity of 2 nM in the

olfactory bulb and neocortex of wild-type mice and of 30 nM

in the habenula of knockout mice, suggesting that binding in

the habenula might be accounted for by 5-ht5b receptors

(Waeber et al., 1998). Those results were somewhat similar

to those obtained using an in situ hybridization assay, in

which the 5-ht5a receptor mRNAwas located predominantly

in the cerebral cortex, the hippocampus, the habenula, the

olfactory bulb, and the granular layer of the cerebellum of

the mouse (Plassat et al., 1992). Reverse transcription-

polymerase chain reaction of the human 5-ht5a receptor

showed expression of mRNA in many brain areas, but none

in peripheral tissues (Rees et al., 1994).

5.1. Functional coupling of the 5-hydroxytryptamine5receptors to signaling pathways

As of yet, the 5-ht5 receptors have not been convincingly

linked to specific physiological effects or signal transduction

cascades in mammalian cells. For example, when expressed

in COS-7 cells and NIH 3T3 cells, 5-ht5 receptors were

unable to modulate AC activity (Plassat et al., 1992). Two

studies have suggested that 5-ht5a receptors might be capable

of inhibiting forskolin-stimulated cAMP accumulation. Car-

son et al. (1996) presented evidence that the 5-ht5a receptor

heterologously expressed in C6 glioma cells could inhibit

cAMP accumulation. Similarly, when the 5-ht5a receptor was


expressed at very high levels in HEK 293 cells, it was shown

to inhibit cAMP accumulation (Francken et al., 1998).

Putative 5-ht5a/5-ht5b receptor binding to [125I]LSD in the

brain (Waeber et al., 1998) and transfected cells (Plassat et al.,

1992) is GTP-sensitive, suggesting that these receptors do

couple to G-proteins. However, the specific G-proteins to

which these receptors couple, their downstream signals, and

physiological effects remain elusive.


Two groups cloned the rat 5-HT6 receptor cDNA in 1993,

although there was disagreement over the sequence of this

receptor (Monsma et al., 1993; Ruat et al., 1993a). This was

subsequently resolved as a sequencing error after the cloning

of the human 5-HT6 receptor in 1996 (Kohen et al., 1996).

The human 5-HT6 receptor is a 440 amino acid protein. The

gene contains two introns that correspond to regions of the

putative i3 and e3 loops (Monsma et al., 1993; Ruat et al.,

1993a). The gene for the receptor maps to the human

chromosome region 1p35-p36 (Kohen et al., 1996). The

5-HT6 receptor stimulates AC and has high affinity for

typical and atypical antipsychotics, including clozapine.

The receptor is expressed in several brain regions, most

prominently in the caudate nucleus, the olfactory tubercle,

the striatum, the hippocampus, and the nucleus accum-

bens (Gerard et al., 1996, 1997; Grimaldi et al., 1998;

Sleight et al., 1998). Low levels of 5-HT6 receptor

mRNA are also expressed in the adrenal gland and the

stomach (Monsma et al., 1993; Ruat et al., 1993a).

Surprisingly, 5-HT6 receptors appear to regulate cholin-

ergic (rather than dopaminergic) neurotransmission in the

brain, implicating it as a target for the treatment of learning

and memory disorders (Bourson et al., 1998; Branchek &

Blackburn, 2000).


adenylyl cyclase

Transfection studies have shown that the 5-HT6 receptor

activates AC (Ruat et al., 1993a; Kohen et al., 1996; Baker

et al., 1998; Grimaldi et al., 1998). 5-HT6-like receptors

have been shown to stimulate AC in striatal neurons in

culture (Sebben et al., 1994) and in pig caudate membranes

(Schoeffter & Waeber, 1994). When transfected into HEK

293 cells, the 5-HT6 receptor stimulates AC5, a Gs-sensitive

AC, but not AC1 or AC8, which are CaM-stimulated ACs.

In contrast, 5-HT7 receptors expressed in the same cells

could also activate AC1 and AC8 (Baker et al., 1998).

6.2. The 5-hydroxytryptamine6 receptor splice variants

Because of the presence of introns in the putative i3 and

e3 loops of the 5-HT6 receptor, alternative splice variants of

this receptor could exist. Thus far, only two truncation

mutants have been identified. The first is expressed in brain,

but is probably not functional as it deletes the entire seventh

transmembrane region of the receptor (Monsma et al.,

1993). Another truncation mutant of the human 5-HT6

receptor in which the protein is prematurely terminated in

the third transmembrane region has been shown to encode a

nonfunctional protein (Olsen et al., 1999).


The 5-HT7 receptor is the third 5-HT receptor subtype

shown to couple to Gs (Bard et al., 1993; Lovenberg et al.,

1993a; Plassat et al., 1993; Ruat et al., 1993b; Shen et al.,

1993). It is highly expressed in the CNS, especially in the

hippocampus, the hypothalamus, and the neocortex. It has

been speculated to participate in the control of circadian

rhythm because it is expressed in the suprachiasmatic

nucleus (Lovenberg et al., 1993a; Stowe & Barnes, 1998).

The 5-HT7 receptor is also expressed in glial cells (Hirst

et al., 1997; Shimizu et al., 1996), the spleen (Shen et al.

1993), vascular smooth muscle (Becker et al., 1992; Bard

et al., 1993; Ullmer et al., 1995; Schoeffter et al., 1996), and

the intestine (Bard et al., 1993). It has a high affinity for

atypical antipsychotic agents, and it may mediate some of

their effects (Shen et al., 1993). It is also expressed in the

periphery, where it mediates relaxation of smooth muscle in

various organs (Eglen et al., 1997).

5-HT7 receptors have been isolated from a number of

mammalian species (Bard et al., 1993; Lovenberg et al.,

1993a; Meyerhof et al., 1993; Plassat et al., 1993; Ruat

et al., 1993b; Shen et al., 1993; Tsou et al., 1994) and

also from X. laevis (Nelson et al., 1995). These receptors

appear to be homologues to the fruit fly 5-HTdro1 receptor

(Witz et al., 1990). The human 5-HT7 receptor initially was

reported to be a protein of 445 amino acids, with 57%

homologywith theDrosophila melanogaster 5-HTdro1 recep-

tor in the transmembrane regions, but only 39–53% homo-

logy with cloned human 5-HT1, 5-HT2, 5-HT5, and 5-HT6

receptors. Surprisingly, there is only 39% homology with

the 5-HT6 receptor within the transmembrane regions (Bard

et al., 1993). The human 5-HT7 receptor gene is located on

chromosome 10 (10q21-q24) (Gelernter et al., 1995), and

contains two introns (Ruat et al., 1993b; Erdmann et al.,

1996; Heidmann et al., 1997).

7.1. The 5-hydroxytryptamine7 receptor splice variants

The presence of introns in the 5-HT7 receptor gene is

significant in that a number of functional splice variants of

this receptor have been identified. No splice variants have

been reported for the first intron, which is in the putative i2

loop of the receptor. The second intron corresponds to the

carboxyl terminus of the 5-HT7 receptor, from which at least


four functional splice variants have been documented. The

first clue that functional splice variants existed came from

the observation that the sequence identified by Lovenberg

and colleagues was truncated by 13 amino acids, compared

with other cloned sequences, and that the truncation

occurred at the second intron (Bard et al., 1993; Lovenberg

et al., 1993a; Shen et al., 1993). Subsequently, four splice

variants, termed 5-HT7a, 5-HT7b, 5-HT7c, and 5-HT7d, were

identified by several groups (Heidmann et al., 1997, 1998;

Jasper et al., 1997; Stam et al., 1997). The 5-HT7a, 5-HT7b,

and 5-HT7c receptor isoforms have been shown to be

expressed in rats, whereas the 5-HT7a, 5-HT7b, and 5-HT7d

receptor isoforms have been shown to be expressed in

humans (Heidmann et al., 1998). The three human splice

variants encode proteins of 448 (5-HT7a), 435 (5-HT7b), and

479 (5-HT7d) amino acids.

The functional consequences of the individual splice

variants are not clear, although all of them seem to be able

to stimulate AC (Jasper et al., 1997; Stam et al., 1997;

Heidmann et al., 1998). However, because the different

variants may have differing numbers of phosphorylation

sites, their regulation by kinases may be different. An

additional difference in the splice variants is the presence

or absence of PDZ motifs in the distal carboxyl terminus.

The 5-HT7a and 5-HT7d receptors do not have a PDZ

motif, whereas the 5-HT7b and 5-HT7c receptors have

group II and group I PDZ motifs, respectively (Hamblin

et al., 1998).


adenylyl cyclase

Transfection studies have shown that the 5-HT7 receptor

stimulates AC in mammalian (Bard et al., 1993; Lovenberg

et al., 1993a; Plassat et al., 1993; Ruat et al., 1993b; Shen

et al., 1993; Tsou et al., 1994; Heidmann et al., 1997, 1998;

Stam et al., 1997) and insect Sf9 cells (Hirst et al., 1997).

Presumably, most of the effects of the 5-HT7 receptor are

mediated through coupling to Gs. In that regard, the i3 loop

of the 5-HT7 receptor has been shown to be critical in

coupling to G-proteins (Obosi et al., 1997). The 5-HT7a

receptor stimulates several forms of AC, including Gs-sen-

sitive AC5 and AC1 and AC8 (Baker et al., 1998). The ability

of the 5-HT7a receptor to activate those latter two isoforms of

AC raises the issue of whether this receptor can also couple to

G-proteins other than Gs. Baker et al. (1998) partially inves-

tigated the question by demonstrating that activation of the

receptor resulted in increases in intracellular Ca2 + , which

is consistent with the known Ca2 + /CaM sensitivity of AC1

and AC8 (Mons et al., 1998; Taussig & Zimmermann,

1998; Hurley, 1999). However, this effect was independent

of PKC, phosphoinositide turnover, and Gi-proteins (Baker

et al., 1998). These results are very intriguing in light of

studies showing that 5-HT can activate Ca2 + -stimulated

AC in the rat cerebral cortex and hippocampus (Mork &

Geisler, 1990).

7.3. The 5-hydroxytryptamine7 receptor activates the

extracellular signal-regulated kinase

Errico et al. (2001) recently reported that 5-HT7

receptors endogenously expressed by cultured rat hippo-

campal neurons stimulate the MAP kinase ERKs ERK1

and ERK2. Details of the signaling pathway used by the

receptor to activate ERK remain to be elucidated, but the

stimulation of ERK was not sensitive to pertussis toxin

and, therefore, is unlikely to involve Gi/o-proteins (Errico

et al., 2001).

7.4. The 5-hydroxytryptamine7 receptor

stimulates vasorelaxation

The 5-HT7 receptor stimulates vasorelaxation (Ullmer

et al., 1995; Terron, 1996; Villalon et al., 1997). The signaling

pathway involved in vasorelaxation by the 5-HT7 receptor is

not known, but it has been hypothesized to involve release of

NO (Morecroft & MacLean, 1998) or cAMP-induced inhibi-

tion of myosin light chain kinase in vascular smooth muscle

cells (Ullmer et al., 1995).

7.5. The 5-hydroxytryptamine7 receptor modulates

slow afterhyperpolarization

The 5-HT7 receptor has been implicated in the inhibition

of Ca2 + -spike-induced slow afterhyperpolarization ampli-

tude in CA3 hippocampal neurons, although the signaling

pathway used to modulate this conductance is not known

(Bacon & Beck, 2000). In contrast, Chapin and Andrade

(2000, 2001a, 2001b) have shown that the 5-HT7 receptor

can actually stimulate afterdepolarization. They performed

detailed studies of the regulation of afterhyperpolarization

by the 5-HT7 receptor in neurons from the anterodorsal

nucleus of the thalamus (Chapin & Andrade, 2001a), and

showed that the signal was mediated by cAMP and by the

hyperpolarization-activated nonselective cation current

(Chapin & Andrade, 2001b). Furthermore, the afterdepola-

rization was independent of PKA (Chapin & Andrade,

2001b) or alterations in cellular Ca2 + levels (Chapin &

Andrade, 2000), suggesting that novel signal transduction

pathways may mediate this effect.

8. Conclusion

The rich diversity of coupling of the 5-HT receptors to

distinct (and sometimes opposing) signaling pathways is

becoming more broadly appreciated as a mechanism of

‘fine-tuning’’ receptor response to the requirements of the

specific cells and tissues in which they are expressed. The

diversity of signaling is mediated by a large number of 5-HT

receptors (14 genomically encoded) and their variants (over

20 splice variants or variants resulting from mRNA editing),

and also by cell-specific and ligand-specific variables. The


diversity of signaling is so staggering that one naturally

might ask: ‘‘What is the purpose of this immense diversity of

signaling mechanisms coupled to 5-HT receptors?’’ Unfortu-

nately, there currently are no clear-cut answers to this

fundamental question. One of us reviewed this topic several

years ago, and many of the points that were raised in that

review remain pertinent today (Raymond, 1995). We will

speculate somewhat on this issue in the next two paragraphs.

The diversity in 5-HT receptor signals may provide

different cells with the capacity to determine the specific

effectors that are modulated by 5-HT receptors, based on

the intrinsic or variable needs of the cells or the organs in

which they reside. Thus, different cell types could respond

differently to the same stimulus, based on their anatomical

location, physiological state, and functions. These diffe-

rential responses in distinct cell types need not be haphaz-

ard; they would most likely be coordinated into some type

of ‘‘response network.’’ For example, glial cells and

neurons could intrinsically coordinate their responsiveness

to 5-HT (or other 5-HT receptor ligands), based on their

complements of 5-HT receptors, G-proteins, and effectors.

This makes sense, as these cell types should be intrins-

ically able to function in a coordinated manner. Their

coordinated responses should also be plastic, in that they

can be shaped by physiological alterations, such as hypoxia

or hormonal influences.

Both the coordination and plasticity of cellular res-

ponses to 5-HT receptors could be influenced by variables

such as (1) the types and numbers of receptors present in

each cell type; (2) the subcellular localizations of the

receptors and their targets into macrodomains or organ-

elles; (3) physical or functional compartmentalization of

the signaling components into microdomains; (4) differ-

ential and/or overlapping sensitivities to various ligands;

(5) differential rates of receptor synthesis, internalization,

degradation, and desensitization; (6) differential signaling

from different ligands acting through single receptor sub-

types due to ‘‘agonist-directed trafficking;’’ (7) the pres-

ence or absence of receptor reserve; (8) different levels of

spontaneous (non-agonist-mediated) receptor activity; (9)

co-stimulation with other receptor types; (10) non-G-pro-

tein-mediated signals; and (11) the presence or absence of

regulatory factors. These same differences could also be

applied to individual G-proteins and effectors. Moreover, all

of those variables need to be recognized as dynamic. Thus,

cells can modify their capacity for signaling from 5-HT

receptors to effectors in order to produce distinct (or even

opposing) responses. Thus, the specific response of a cell to

5-HT will be determined as the sum of many variables. That

is why signal transduction studies performed in transfected

cells ultimately must be validated contextually in cells,

organs, or animals in which the 5-HT receptors are endoge-

nously expressed.

This review has highlighted some fascinating new

insights into 5-HT receptor signaling that have resulted

from multiple lines of investigation over the last decade.

Substantial recent progress has been made in defining the

potential diversity of signaling from 5-HT receptors. The

discovery process has been accelerated by the cloning of

cDNA and genes for 5-HT receptors, by transfection

studies, by the development of new ligands, by the

creation of transgenic and receptor knockout animals,

and by the generation of receptor-specific tools, such as

antibodies and selective mRNA probes. Despite the accel-

erating pace of exciting discoveries in this field, one is

struck by a sense that the most exciting new discoveries

are yet to come.

Acknowledgements

The authors were supported by grants from the Depart-

ment of Veterans Affairs (Merit Awards to M.N.G. and

J.R.R. and a REAP Award to Y.V.M., A.G., J.R.R., G.C.,

and M.N.G.), the National Institutes of Health (DK52448

and DK54720 to J.R.R., DK053981 to T.W.G., and

DK02694 to Y.V.M.), and a laboratory endowment jointly

supported by the M.U.S.C. Division of Nephrology and

Dialysis Clinics, Incorporated (J.R.R.). A.G. and M.N.G.

were Associate Investigators of the Department of Veterans

Affairs during the composition of this manuscript.

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Multiplicity of mechanisms of serotonin receptor signal transduction

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