5-Hydroxytryptamine receptors: Introduction


The nomenclature for 5-hydroxytryptamine (5-HT, serotonin) receptors has undergone considerable evolution since the first systematic consensus review in 1985. In the late 1980’s and early 1990’s the expansion in the identification of gene products that displayed characteristics of 5-HT receptors provided primary structures that largely underpins the current classification system. Whilst it has been nearly two decades since the last 5-HT GPCR (G-protein coupled receptor) gene was sequenced, in more recent times the proliferation of subunits within the 5-HT3 receptor family – a member of the cys-loop LGIC (ligand-gated ion channel) superfamily - has necessitated further additions to the 5-HT receptor family. That 5-HT receptors provide members of both GPCR and LGIC superfamilies is a unique feature amongst monoamine neurotransmitters and local hormones.

The present NC-IUPHAR classification is primarily based on structural data along with transductional and operational information; although the growing appreciation of the promiscuous nature of receptors, both in terms of their coupling to multiple transduction pathways and their ability to form heterodimers, necessitates that primary structure essentially defines the positioning of the gene product within the receptor family, with elevation to full receptor status of the protein subsequent to a robust demonstration of function in native tissue.

5-HT receptors are distributed amongst seven distinct families, with some families containing multiple receptors, classified primarily on their similar amino acid sequences and structural properties. Further 5-HT receptor heterogeneity is generated through alternative splicing (5-HT3, 5-HT4 and 5-HT7 receptors), RNA editing (5-HT2C receptors) and the putative formation of heterodimers (e.g. the 5-HT4 receptor with the beta-2 adrenoreceptor).

The 5-HT1 Receptors

The 5-HT1 receptor family comprises five different receptors (5-HT1A, 5-HT1B, 5-HT1D, 5-ht1e, 5-HT1F), which share 40-63% amino acid sequence identity and can couple to Gi/Go to inhibit cAMP formation, although signaling via other transduction systems are known (e.g. 5-HT1A receptor activates G-protein-gated inwardly rectifying K+ channel [GIRK]). One of the 5-HT1 receptor class, the 5-ht1e receptor, is yet to achieve receptor status since a robust response mediated via the protein is yet to be reported in the literature; lower-case appellation is used to denote this. 5-HT1A and 5-HT1B receptors act as somatodendritic and terminal autoreceptors, respectively; however, these receptors are also expressed throughout the CNS.

A number of well-defined selective agonists (e.g. 8-OH-DPAT [5-HT1A receptor], PNU 109291 [5-HT1D receptor], LY 344864 [5-HT1F receptor]) and antagonists (e.g. WAY100635 [5-HT1A receptor], SB236057 [5-HT1B receptor], SB714786 [5-HT1D receptor]), are available to selectively probe some individual members of the 5-HT1 receptors.

Clinical significance
5-HT1A receptors are targeted by the anxiolytic drug, buspirone, which is a partial agonist. Various ‘triptans’ (e.g. sumitriptan and zolmitriptan) are used to treat acute migraine attack, these drugs are 5-HT1B/5-HT1D receptor agonists, with some also having agonist activity at the 5-HT1F receptor.

The 5-HT2 Receptors

The 5-HT2 family comprise three receptors; 5-HT2A, 5-HT2B and 5-HT2C that exhibit 42-51% overall amino acid sequence identity and can couple to Gq/G11 to increase the hydrolysis of inositol phosphates and elevate cytosolic [Ca2+]. In addition, Gq/G11 coupling to other transduction pathways is apparent (e.g. PI3K/Akt and ERK). The 5-HT2C receptor is prone to RNA editing, resulting in multiple distinct isoforms that may display altered transduction efficiency as well as preferred transduction pathway coupling. This RNA editing can be regulated by psychotropic drugs, thereby altering the functionality of these receptors in a region-specific manner in brain. These receptors demonstrate several intriguing and subtle pharmacological properties that have been studied in depth. 5-HT2 receptors display agonist-directed signaling or “biased agonism” in which the same agonist in different cell types or different agonists in the same cell type will differentially activate multiple, distinct signaling pathways.

Preliminary evidence indicates that 5-HT2B receptors can act as autoreceptors in serotonin neurons; these receptors have also been found to interact reciprocally with tyrosine kinase receptors to induce mitogenic effects at very low concentrations of 5-HT. There are several examples of 5-HT2 receptors dimerizing both to like and dissimilar receptors. An intriguing reciprocal interaction occurs between 5-HT2A and mGluR2 glutamate receptors in cerebral cortex, whereby activation of the glutamate receptor inhibits the function of 5-HT2A receptors only when activated by hallucinogenic (such as LSD) but not non-hallucinogenic 5-HT2A receptor agonists (such as lisuride).

Selective antagonists for each of the 5-HT2receptors are available (e.g. volinanserin [5-HT2A receptor], RS 127445 [5-HT2B receptor], SB 242084 [5-HT2C receptor]), whereas selective agonists are limited (e.g. lorcaserin is an agonist at 5-HT2C receptors although displays only ~15-fold selectivity over the 5-HT2A receptor).

Clinical significance
These receptors have a complex and interesting role in psychotropic pharmacology. Some hallucinogens display “biased agonism” at 5-HT2A receptors. A number of atypical antipsychotics are 5-HT2A/C antagonists or inverse agonists (e.g. asenapine, chlorpromazine, pimozide, clozapine, risperidone), which may contribute to the efficacy of these drugs, many of which display wide ranging poly-pharmacology. Transgenic and pharmacological data suggest that increased appetite and metabolic syndrome may be associated with 5-HT2C receptor blockade. In addition, non-selective 5-HT receptor antagonists such as methysergide are used in the prophylactic treatment of migraine. Activation of 5-HT2B receptors in heart may lead to cardiac valvulopathy; this may be a risk for both non-selective 5-HT releasers (e.g. fenfluramine; which led to withdrawal from the clinic) or selective 5-HT2B receptor agonists.

The 5-HT3 Receptor

The 5-HT3 receptor contrasts all other identified 5-HT receptors, being a cys-loop ligand-gated cation channel displaying close structural relationships with nicotinic acetylcholine, GABA-A, glycine and Zn2+-activated ionotropic receptors. The 5-HT3 receptor mediates fast depolarizing responses that are prone to desensitization with prolonged agonist activation. The receptor complex is comprised of five subunits that surround the integral ion channel in a ‘ring doughnut’ arrangement. The first subunit to be identified, 5-HT3A subunit, efficiently forms a functional homomeric receptor that displays many of the characteristics of some native 5-HT3 receptors. Further subunits have been identified (5-HT3B, 5-HT3C, 5-HT3D, 5-HT3E subunits), which do not appear to form functional homomeric receptors although assemble into heteromeric 5-HT3 receptors along with the 5-HT3A subunit.

A range of selective 5-HT3 receptor agonists (e.g. SR57227A, DDP733 [partial agonist]) and antagonists (e.g. ondansetron, granisetron) are available. In common with other members of the cys-loop LGIC family, 5-HT3 receptors possess allosteric modulatory sites that influence receptor function.

Clinical significance
5-HT3 receptor antagonists are effective anti-emetic drugs (e.g. ondansetron, granisetron, palonosetron) and also offer symptomatic relief from diarrhoea-predominant irritable bowel syndrome (IBS-d; e.g. alosetron, ramosetron). For further information see: 5-HT3.

The 5-HT4 Receptor

The 5-HT4 receptor is a GPCR that couples via Gs to increase cAMP production. The structure displays less than 34% amino acid sequence identity to other 5-HT GPCRs justifying the separate family. At least 10 splice variants have been identified.

Selective agonists (e.g. RS 67506 [partial agonist]) and antagonists (e.g. SB 204070) are available.

Clinical significance
5-HT4 receptor agonists (e.g. cisapride, tegaserod) were effective drugs reducing the symptoms of gastro-oesophageal reflux, constipation and constipation-predominant irritable bowel syndrome (IBS-c), before they were withdrawn due to cardiovascular side-effects.

The 5-ht5 Receptors

Two genes have been identified that give rise to 5-ht5a and 5-ht5b proteins with structures consistent with GPCRs although in humans the 5-ht5b gene is a pseudogene since a stop codon has evolved that would, if expressed, result in a truncated protein devoid of key functional moieties of the receptor. The predicted protein sequences display less than 38% amino acid sequence identity to other 5-HT GPCRs, thus clearly distinguishing the 5-ht5a protein from other 5-HT receptors.

5-ht5a is yet to receive receptor status since no robust response signal in native tissue has been described. Native 5-ht5a protein would appear G-protein coupled and recombinant expression allows coupling via various transduction systems including the G-protein mediated inhibition of adenylate cyclase. A selective antagonist based on recombinant protein function has been identified (SB699551-A).

The 5-HT6 Receptor

The 5-HT6 receptor is a GPCR that couples via Gs to increase cAMP production although additional transduction pathways have been proposed. The receptor is structurally differentiated from the other 5-HT receptors with less than 34% amino acid sequence identity. Various selective 5-HT6 receptor antagonists have been described (e.g. SB742457) and selective agonists are becoming available (e.g. EMD386088).

EMDT, EMD386088, and WAY181,187 are relatively selective 5-HT6 receptor agonists, and a number of selective antagonists have also been developed including SB399885, SB258585 and Ro4368554.

Clinical significance
A number of non-selective drugs used to treat schizophrenia (e.g. asenapine, chlorpromazine, olanzepine, clozapine, zotepine), also display high affinity for the 5-HT6 receptor, although the consequences of this are not clear. These receptors are selectively expressed in the CNS, but mouse brain has a notably different regional pattern of expression in comparison to humans or rats. Relatively selective 5-HT6 antagonists induce precognitive effects in animal models, but little data has been generated in clinical populations.

The 5-HT7 Receptor

The 5-HT7 receptor is a GPCR that couples via Gs to increase cAMP production with some other transduction pathways also implicated in receptor function (e.g. ERK, Galpha12/RhoA/Cdc42). The structure displays less than 39% amino acid sequence identity to other 5-HT receptors. Several splice variants have been described.

Various selective 5-HT7 receptor agonists (e.g. LP-12, AS-19 [partial agonist]) and antagonists (e.g. SB 269970, SB656104-A) have been described.

Clinical significance
Similar to the 5-HT6 receptor, various non-selective psychotropic drugs also display high affinity for the 5-HT7 receptor (e.g. asenapine, clozapine, pimozide), although the consequences of this interaction are also not clear.

A potential orphan 5-HT receptor

5-HT1P receptor is an unofficial name which has been given to a receptor that appears to influence gut peristalsis. The endogenous ligand (5-HT) displays a high affinity, whilst 5-hydroxyindalpine is a potent and selective agonist and N-acetyl-5-hydroxytrytophyl-5-hydroxytryptophanamide an antagonist of 5-HT1P receptor mediated responses. The operational data does not correspond to any known individual monoamine receptor and it has been speculated that the 5-HT1P receptor may arise from heterodimerisation.

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