5-HT3 receptors: Introduction


The 5-hydroxytryptamine type-3 (5-HT3) receptor was first described as the ‘M’ receptor in a seminal analysis of the contractile action of 5-HT upon the guinea-pig isolated ileum preparation [26]. The current appellation was applied following the reclassification of 5-HT receptors performed by Bradley et al. [9] and was formally endorsed by NC-IUPHAR in 1994 [29]. Unlike all other vertebrate 5-HT receptors, which are G-protein coupled [29-30], the 5-HT3 receptor is a cation-selective ligand-gated ion channel of the pentameric ligand-gated ion channel (pLGIC) family that includes the nicotinic acetylcholine, γ-aminobutyric acid-type-A and strychnine-sensitive glycine receptors and a less extensively studied Zn2+-activated ion channel [3,18,21,33,35,38,46,55]. The activation of neuronal 5-HT3 receptors causes the depolarization of presynaptic nerve endings resulting in modulation of the release of several neurotransmitters including γ-aminobutyric acid, glutamate, cholecystokinin, acetylcholine, dopamine noradrenaline, 5-HT and substance P [13,23,42]. In the lateral amygdala and neocortex, postsynaptic 5-HT3 receptors contribute to fast excitatory neurotransmission [25,53]. The native channel conducts monovalent metal cations in a non-selective manner [33,53] and is also permeable to Ca2+ [62-63], although estimates of relative permeability to Ca2+ vary in the literature and may reflect differences in the subunit composition of the receptor [17,41].


In common with all members of the superfamily, 5-HT3 receptors comprise a pentameric assembly of subunits that surround a central, water-filled, transmembrane ion channel [5,8,27]. Individual subunits (with the exception of certain splice variants) contain a large extracellular N-terminal domain that embodies components of the ligand binding site located at the subunit interfaces. The four transmembrane domains (M1-M4) are connected by intracellular (M1-M2 and M3-M4) and extracellular (M2-M3) loops, of which the M3-M4 linker is the most extensive, and the polypeptide terminates in a short extracellular C-terminus [3,45-46,56]. M2 and short flanking sequences contribute to the lining of the ion channel [13,45] and there is evidence that a region of the M3-M4 loop also contributes to the permeation pathway [3,19,45], although this region is not essential for receptor function, or mono-valent cation, versus -anion, selectivity [36]. Five human 5-HT3 receptor subunits, termed 5-HT3A [6,17], 5-HT3B [22,39], 5-HT3C [22,43], 5-HT3D [22,43], and 5-HT3E [22,43] have been cloned, but only homo-pentamers of the 5-HT3A subunit [i.e. (5HT3A)5] and heteromers of the 5-HT3A and 5-HT3B subunit [i.e. 5-HT3AB] that in vitro assemble with the stoichiometry (5-HT3A)2(5-HT3B)3 [5] have been sufficiently characterised to be tabulated at present. In addition, although evidence has recently been adduced for the co-assembly of 5-HT3C, 5-HT3D and 5-HT3E with 5-HT3A subunits in vitro [28,44], there is no published evidence that the HTR3C, HTR3D and HTR3E genes are translated to protein in vivo. Further potential diversity within the 5-HT3 receptor class occurs with the possibility of alternatively spliced transcripts of the human HTR3A [10,28], HTR3C [28], HTR3D [28]and HTR3E [28,44] genes and single nucleotide polymorphisms that impact upon receptor expression and/or function [32,32,60]. In addition, distinct isoforms of the 5-HT3B subunit may be produced by activation of alternative promoters in the HTR3B gene [57].


Responses to 5-HT attributable to 5-HT3 receptor activation can be distinguished from those mediated by G-protein-coupled 5-HT receptors by numerous selective and competitively acting antagonist compounds. These include bemesetron (MDL72222 [24]), tropisetron (ICS205-930 [47], ondansetron (GR38032F [12]), zacopride (AHR11190B [51]), dolasetron (MDL73147 [7]), granisetron (BRL43694 [50]), cilansetron [58], ramosetron (YM060 [1]) and alosetron (GR68755 [14]). Palonosetron (RS 25259-197 [61] ) has been described as an allosteric antagonist [48]. Such agents typically bind to native and recombinant 5-HT3 receptors with high affinity [56] and good selectivity. However, zacopride also activates 5-HT4 receptors and at high concentrations tropisetron acts as an antagonist of 5-HT4 receptors. The in vitro pharmacology of 5-HT3 receptor antagonists is described in detail in several reviews [4,15,56]. Activation of 5-HT3 receptors can be achieved, with varying degrees of selectivity, by compounds that include 2-methyl-5-HT [47], SR57227 (4-amino-(6-chloro-2-pyridyl)-1-piperidine hydrochloride), which crosses the blood-brain barrier [2], and a range of arylbiguanides, the most extensively studied of which are 1-phenylbiguanide and its 3-chloro-substitued derivative, meta-chlorophenylbiguanide [40]. The potency and efficacy of individual compounds relative to 5-HT differs considerably between experimental preparations (see below). Differences in the degree of ‘receptor reserve’ inherent in some experimental paradigms and intra-species variation in the pharmacological properties of the 5-HT3 receptor are confounding issues in this respect [6,11,34,37,39,41]. Recombinant 5-HT3A and 5-HT3AB receptors differ profoundly in their biophysical properties [22,46], but the inclusion of the 5-HT3B subunit has only a minor influence upon the affinity of most 5-HT3 receptor selective ligands that have been examined [3,17,46,59] (however please see [22]). Similarly, the assembly of 5-HT3A with 5-HT3C, 5-HT3D, or 5-HT3E subunits does not cause a significant change in ligand binding profile [28,44]. Limited pharmacological discrimination between 5-HT3A and 5-HT3AB receptors can be made with the non-selective compounds (+)-tubocurarine [17], picrotoxin [16], methadone [20], and some antimalarial drugs [54]. 5-HT3A and 5-HT3AB receptors differ in their allosteric regulation by some general anaesthetic agents [52], small alcohols [49] and indoles [31].

Classic in vitro preparations used in the development of 5-HT3 receptor selective ligands and to study the characteristics of native 5-HT3 receptors include the guinea-pig isolated ileum [12,24,26,47,50], rat and guinea-pig isolated vagus nerve [12], isolated superior cervical and nodose ganglia of several species [41] and the rabbit isolated heart [24,50]. In addition, numerous clonal cell lines also express a 5-HT3 receptor [33,38,53] and represent a source from which the protein can be purified [8]. Antagonist potency in vivo can be assessed by blockade of the Bezold-Jarisch effect of intravenous 5-HT (transient bradycardia and hypotension mediated by the vagus nerve) delivered as a bolus to the anaesthetised rat [24]. Functional assays applicable to recombinant 5-HT3 receptors are detailed in the tables.


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