General

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-HT_2C 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-HT_1A, 5-HT_1B, 5-HT_1D, 5-ht_1e, 5-HT_1F), 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-HT_1A receptor activates G-protein-gated inwardly rectifying K+ channel [GIRK]). One of the 5-HT₁ receptor class, the 5-ht_1e 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-HT_1A and 5-HT_1B receptors act as somatodendritic and terminal autoreceptors, respectively; however, these receptors are also expressed throughout the CNS.

Pharmacology
A number of well-defined selective agonists (e.g. 8-OH-DPAT [5-HT_1A receptor], PNU 109291 [5-HT_1D receptor], LY 344864 [5-HT_1F receptor]) and antagonists (e.g. WAY100635 [5-HT_1A receptor], SB236057 [5-HT_1B receptor], SB714786 [5-HT_1D receptor]), are available to selectively probe some individual members of the 5-HT1 receptors.

Clinical significance
5-HT_1A 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-HT_1B/5-HT_1D receptor agonists, with some also having agonist activity at the 5-HT_1F receptor.

The 5-HT₂ Receptors

The 5-HT₂ family comprise three receptors; 5-HT_2A, 5-HT_2B and 5-HT_2C that exhibit 42-51% overall amino acid sequence identity and can couple to G_q/G₁₁ to increase the hydrolysis of inositol phosphates and elevate cytosolic [Ca²⁺]. In addition, G_q/G₁₁ coupling to other transduction pathways is apparent (e.g. PI3K/Akt and ERK). The 5-HT_2C 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-HT_2B 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-HT_2A and mGluR₂ glutamate receptors in cerebral cortex, whereby activation of the glutamate receptor inhibits the function of 5-HT_2A receptors only when activated by hallucinogenic (such as LSD) but not non-hallucinogenic 5-HT_2A receptor agonists (such as lisuride).

Pharmacology
Selective antagonists for each of the 5-HT₂receptors are available (e.g. volinanserin [5-HT_2A receptor], RS 127445 [5-HT_2B receptor], SB 242084 [5-HT_2C receptor]), whereas selective agonists are limited (e.g. lorcaserin is an agonist at 5-HT_2C receptors although displays only ~15-fold selectivity over the 5-HT_2A receptor).

Clinical significance
These receptors have a complex and interesting role in psychotropic pharmacology. Some hallucinogens display “biased agonism” at 5-HT_2A receptors. A number of atypical antipsychotics are 5-HT_2A/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-HT_2C receptor blockade. In addition, non-selective 5-HT receptor antagonists such as methysergide are used in the prophylactic treatment of migraine. Activation of 5-HT_2B 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-HT_2B 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.

Pharmacology
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 G_s 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.

Pharmacology
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-ht_5a and 5-ht_5b proteins with structures consistent with GPCRs although in humans the 5-ht_5b 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-ht_5a protein from other 5-HT receptors.

5-ht_5a is yet to receive receptor status since no robust response signal in native tissue has been described. Native 5-ht_5a 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).

Pharmacology
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.

Pharmacology
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-HT_1P 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-HT_1P receptor mediated responses. The operational data does not correspond to any known individual monoamine receptor and it has been speculated that the 5-HT_1P receptor may arise from heterodimerisation.