Molecular, pharmacological and functional diversity of 5-HT receptors
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-HT3B) and possibly a third (5-ht3C) subunit for the 5-HT3 receptor. Nevertheless, multiple splice variants (5-HT4, 5-HT7) or RNA edited isoforms (5-HT2C) have been described, whilst there is evidence that amongst the heptahelical 5-HT receptors, homo- and heterodimerisation (5-HT1B/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-HT1B and 5-HT1D receptors, or oleamide, which acts on several 5-HT receptors (including 5-HT2A/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-HT1A, 5-HT1B, 5-HT1D, 5-ht1E and 5-ht1F), which, in humans, share 40–63% overall sequence identity and couple preferentially, although not exclusively, to Gi/o to inhibit cAMP formation (see Table 1, Table 2). The 5-ht1E and 5-ht1F receptors are given a lower case appellation to denote that endogenous receptors with a physiological role have not yet been found. In contrast, 5-HT1A, 5-HT1B and 5-HT1D receptors have been
The 5-HT2 receptor class
This class comprises the 5-HT2A, 5-HT2B and 5-HT2C receptors, which exhibit 46–50% overall sequence identity and couple preferentially to Gq/11 to increase the hydrolysis of inositol phosphates and elevate cytosolic [Ca++] (see Table 1, Table 2). The 5-HT2A 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-HT2B 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 GABAA 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-HT4,6,7 receptors
Although the 5-HT4, 5-ht6 and 5-HT7 receptors all couple preferentially to Gs 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-ht5A and 5-ht5B), sharing 70% overall sequence identity, have been found in rodents, whereas the 5-ht5A 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-ht5B 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-HT2C receptor RNA editing
The 5-HT2C 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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