Molecular, pharmacological and functional diversity of 5-HT receptors

doi:10.1016/S0091-3057(01)00746-8

Pharmacology Biochemistry and Behavior

Volume 71, Issue 4, April 2002, Pages 533-554

https://doi.org/10.1016/S0091-3057(01)00746-8 Get rights and content

Abstract

Serotonin (5-hydroxytryptamine, 5-HT) is probably unique among the monoamines in that its effects are subserved by as many as 13 distinct heptahelical, G-protein-coupled receptors (GPCRs) and one (presumably a family of) ligand-gated ion channel(s). These receptors are divided into seven distinct classes (5-HT₁ to 5-HT₇) largely on the basis of their structural and operational characteristics. Whilst this degree of physical diversity clearly underscores the physiological importance of serotonin, evidence for an even greater degree of operational diversity continues to emerge. The challenge for modern 5-HT research has therefore been to define more precisely the properties of the systems that make this incredible diversity possible. Much progress in this regard has been made during the last decade with the realisation that serotonin is possibly the least conservative monoamine transmitter and the cloning of its many receptors. Coupled with the actions of an extremely avid and efficient reuptake system, this array of receptor subtypes provides almost limitless signalling capabilities to the extent that one might even question the need for other transmitter systems. However, the complexity of the system appears endless, since posttranslational modifications, such as alternate splicing and RNA editing, increase the number of proteins, oligomerisation and heteromerisation increase the number of complexes, and multiple G-protein suggest receptor trafficking, allowing phenotypic switching and crosstalk within and possibly between receptor families. Whether all these possibilities are used in vivo under physiological or pathological conditions remains to be firmly established, but in essence, such variety will keep the 5-HT community busy for quite some time. Those who may have predicted that molecular biology would largely simplify the life of pharmacologists have missed the point for 5-HT research in particular and, most probably, for many other transmitters. This chapter is an attempt to summarise very briefly 5-HT receptor diversity. The reward for unravelling this complex array of serotonin receptor–effector systems may be substantial, the ultimate prize being the development of important new drugs in a range of disease areas.

Introduction

Serotonin (5-hydroxytryptamine, 5-HT) produces its effects through a variety of membrane-bound receptors. 5-HT and its receptors are found both in the central and peripheral nervous system (CNS/PNS), as well as in a number of nonneuronal tissues in the gut, cardiovascular system and blood. In evolutionary terms, 5-HT is one of the oldest neurotransmitters and has been implicated in the aetiology of numerous disease states, including depression, anxiety, social phobia, schizophrenia, and obsessive–compulsive and panic disorders; in addition to migraine, hypertension, pulmonary hypertension, eating disorders, vomiting and, more recently, irritable bowel syndrome (IBS).

With the exception of the 5-HT₃ receptor, which is a ligand-gated ion channel, 5-HT receptors belong to the G-protein-coupled receptor (GPCR) superfamily and, with at least 14 distinct members, represent one of the most complex families of neurotransmitter receptors. However, for a number of years, there has been no new addition to the 14 known receptors, with the exception of a second (5-HT_3B) and possibly a third (5-ht_3C) subunit for the 5-HT₃ receptor. Nevertheless, multiple splice variants (5-HT₄, 5-HT₇) or RNA edited isoforms (5-HT_2C) have been described, whilst there is evidence that amongst the heptahelical 5-HT receptors, homo- and heterodimerisation (5-HT_1B/1D) can occur, as reported for other GPCRs. Furthermore, peptide or lipid receptor modulators have been reported, such as 5-HT moduline (Leu–Ser–Ala–Leu (LSAL), a putative product of a chromogranin), which demonstrates selectivity for the 5-HT_1B and 5-HT_1D receptors, or oleamide, which acts on several 5-HT receptors (including 5-HT_2A/2C and 5-HT₇).

Not surprisingly, the 5-HT receptor family has been a long-standing target of intense research, in both the academia and the pharmaceutical industry, even before the complexity of the system was unravelled by molecular cloning. Current efforts pursue in the identification of more potent and selective ligands for the different receptor subtypes. It is anticipated that such selective receptor probes will provide the tools to advance definition of functional effects in situ, be it in vitro or in vivo, and, in addition, lead to enhanced drug treatments with fewer side effects for a variety of disorders. Moreover, molecular genetic approaches offer a complementary strategy for studying distinct 5-HT receptor subtypes via the generation of gene-targeted and transgenic lines of mice with altered expression of 5-HT receptor genes. 5-HT is also a substrate for the 5-HT transporter, itself an important target in the treatment of depression and social phobia; however, the transporter will not be addressed here. Suffice, it is the target for selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, paroxetine and citalopram, which is one of the most important classes of drugs to have emerged during the 20th century.

Section snippets

Current criteria for classifying 5-HT receptors

The classification of 5-HT receptors began in 1957, when it was demonstrated that functional responses of the guinea pig ileum could be partially blocked by morphine (M), whilst the remainder of the response was inhibited by dibenzyline (D). This led Gaddum and Picarelli (1957) to propose a subdivision of these novel receptors naming them M and D receptors, respectively. However, this classification was scrutinised due to the nonspecific effects of these discriminatory ligands on other

The 5-HT₁ receptor class

The 5-HT₁ receptor class is comprised of five receptor subtypes (5-HT_1A, 5-HT_1B, 5-HT_1D, 5-ht_1E and 5-ht_1F), which, in humans, share 40–63% overall sequence identity and couple preferentially, although not exclusively, to G_i/o to inhibit cAMP formation (see Table 1, Table 2). The 5-ht_1E and 5-ht_1F receptors are given a lower case appellation to denote that endogenous receptors with a physiological role have not yet been found. In contrast, 5-HT_1A, 5-HT_1B and 5-HT_1D receptors have been

The 5-HT₂ receptor class

This class comprises the 5-HT_2A, 5-HT_2B and 5-HT_2C receptors, which exhibit 46–50% overall sequence identity and couple preferentially to G_q/11 to increase the hydrolysis of inositol phosphates and elevate cytosolic [Ca⁺⁺] (see Table 1, Table 2). The 5-HT_2A receptor refers to the classical D receptor initially described by Gaddum and Picarelli (1957), which was later defined as the 5-HT₂ receptor by Peroutka and Snyder (1979). The 5-HT_2B receptor mediates the contractile action of 5-HT in the

The 5-HT₃ receptor class: an intrinsic ligand-gated channel

5-HT₃ receptors (M receptors of Gaddum and Picarelli, 1957) have been, based on their overall electrophysiological features and sequence, placed within the ligand-gated ion channel receptor superfamily, similar to the nicotinic acetylcholine or GABA_A receptors (Boess and Martin, 1994). The receptors are found on neurones, of both central and peripheral origin, where they trigger rapid depolarisation due to a transient inward current, subsequent to the opening of nonselective cation channels (Na⁺

Receptors positively coupled to adenylate cyclase: 5-HT_4,6,7 receptors

Although the 5-HT₄, 5-ht₆ and 5-HT₇ receptors all couple preferentially to G_s and promote cAMP formation, they are classified as distinct receptor classes because of their limited (<35%) overall sequence identities (Table 1). This subdivision is recognised as arbitrary and may be subject to future modification. However, the sequence dissimilarity justifies classification into different groups. Although the common approach has been to perform analogy cloning, based on known sequences (e.g. 5-ht₆

Orphan receptors: the putative 5-ht₅ receptors

To date, no evidence has been obtained to confirm that the recombinant 5-ht₅ receptor is expressed in an endogenous setting. Two subtypes of the 5-ht₅ receptor (5-ht_5A and 5-ht_5B), sharing 70% overall sequence identity, have been found in rodents, whereas the 5-ht_5A subtype has been found in humans and mapped to chromosome 7q36.1 Erlander et al., 1993, Matthes et al., 1993, Schanen et al., 1996, Grailhe et al., 2001. The 5-ht_5B receptor gene has been mapped to human chromosome 2q11–q13;

Other putative orphan 5-HT receptors

A number of endogenous 5-HT receptors have been identified and defined in terms of recognitory and/or transductional characteristics, but a corresponding gene product encoding the receptor has yet to be identified. In the absence of structural information enabling unequivocal classification, these receptors are regarded as orphans of the present classification scheme. One of these, the so-called ‘5-HT₁-like’ receptor mediating direct vasorelaxation has been shown to correspond to the 5-HT₇

5-HT_2C receptor RNA editing

The 5-HT_2C receptor is the only GPCR reported so far to be subjected to RNA editing Burns et al., 1997, Fitzgerald et al., 1999. Deamination of one or more adenine bases present at five specific sites in the receptor pre-mRNA, results in conversion of the edited bases to inosine. Upon translation of the mature mRNA, these inosine bases are read as guanine, resulting in an alteration of the amino acids present in the second intracellular loop and the formation of distinct receptor isoforms. RNA

Conclusion

The challenge for the next decade of 5-HT research is to define to what extent the almost incredible diversity in receptors and transporters fulfils specific physiological and/or pathophysiological roles. Since the molecular tools are now in place, it may soon be possible to determine which form of a given receptor is expressed in a given tissue of interest, leading to a better understanding of its effects in situ, rather than relying on measurements made with recombinant receptors. This may

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Molecular, pharmacological and functional diversity of 5-HT receptors

Abstract

Introduction

Section snippets

Current criteria for classifying 5-HT receptors

The 5-HT1 receptor class

The 5-HT2 receptor class

The 5-HT3 receptor class: an intrinsic ligand-gated channel

Receptors positively coupled to adenylate cyclase: 5-HT4,6,7 receptors

Orphan receptors: the putative 5-ht5 receptors

Other putative orphan 5-HT receptors

5-HT2C receptor RNA editing

Conclusion

Trends Pharmacol Sci

J Biol Chem

J Biol Chem

Eur J Pharmacol

Brain Res

Eur J Pharmacol

FEBS Lett

Trends Pharmacol Sci

Neuropharmacology

Neuropharmacology

Brain Res

Eur J Med Chem

Neuropharmacology

Bioorg Med Chem Lett

Eur J Pharmacol

Neuropharmacology

Eur J Pharmacol

Trends Pharmacol Sci

Brain Res

Life Sci

Neuropharmacology

Neuropharmacology

J Biol Chem

Neuroscience (Oxford)

Neuropharmacology

Neuroscience (Oxford)

Eur J Pharmacol

Neuropharmacology

Neuropsychopharmacology

Eur J Pharmacol

Eur J Pharmacol

J Biol Chem

Eur J Pharmacol

Neuropharmacology

Neuroscience

Functional characterization of the recombinant human 5-hydroxytryptamine 7(a) receptor isoform coupled to adenylate cyclase stimulation

J Pharmacol Exp Ther

Electrophysiology of serotonin receptor subtypes and signal tranduction pathways

Serotonin and hallucinogens

Neuropsychopharmacology

Regional changes in density of serotonin transporter in the brain of 5-HT1A and 5-HT1B knockout mice, and of serotonin innervation in the 5-HT1B knockout

J Neurochem

Neurochemical consequences following pharmacological manipulation of central 5-HT4 receptors

L 694247: a potent 5-HT1D receptor agonist

Br J Pharmacol

Structure of the human serotonin 5-HT4 receptor gene and cloning of a novel 5-HT4 splice variant

J Neurochem

Serotonin and lysergic acid diethylamide binding in rat brain membranes: relationship to postsynaptic serotonin receptors

Mol Pharmacol

5-HT1A receptors and the tail-flick response. Spinally localized 5-HT1A receptors postsynaptic to serotoninergic neurons mediate spontaneous tail-flicks in the rat

J Pharmacol Exp Ther

5-HT2C receptor modulation and the treatment of obesity

Diabetes, Obes Metab

Direct evidence for an important species difference in the mechanism of 8-OH-DPAT-induced hypothermia

Br J Pharmacol

Cloning, expression and pharmacology of four human 5-hydroxy tryptamine 4 receptor isoforms produced by alternative splicing in the carboxyl terminus

J Neurochem

Ultrastructure of the 5-hydroxytryptamine 3 receptor

J Neurochem

Exceptionally potent inhibitors of fatty acid amide hydrolase: the enzyme responsible for degradation of endogenous oleamide and anandamide

Proc Natl Acad Sci U S A

[3H]RS-23597-190, a potent 5-hydroxytryptamine4 antagonist labels sigma-1 but not sigma-2 binding sites in guinea pig brain

J Pharmacol Exp Ther

The 5-HT₁ receptor class

The 5-HT₂ receptor class

The 5-HT₃ receptor class: an intrinsic ligand-gated channel

Receptors positively coupled to adenylate cyclase: 5-HT_4,6,7 receptors

Orphan receptors: the putative 5-ht₅ receptors

5-HT_2C receptor RNA editing

Regional changes in density of serotonin transporter in the brain of 5-HT_1A and 5-HT_1B knockout mice, and of serotonin innervation in the 5-HT_1B knockout

Neurochemical consequences following pharmacological manipulation of central 5-HT₄ receptors

L 694247: a potent 5-HT_1D receptor agonist

Structure of the human serotonin 5-HT₄ receptor gene and cloning of a novel 5-HT₄ splice variant

5-HT_1A receptors and the tail-flick response. Spinally localized 5-HT_1A receptors postsynaptic to serotoninergic neurons mediate spontaneous tail-flicks in the rat

5-HT_2C receptor modulation and the treatment of obesity

[³H]RS-23597-190, a potent 5-hydroxytryptamine4 antagonist labels sigma-1 but not sigma-2 binding sites in guinea pig brain