3B but which 3B and that's just one of the questions: the heterogeneity of human 5-HT3 receptors

Abstract

The 5-hydroxytryptamine 3 (5-HT3) receptor is expressed widely in the central and peripheral nervous systems, where it mediates or modulates a wide range of physiological processes. The receptor is targeted by drugs administered for nausea and/or emesis and irritable bowel syndrome and has been proposed as a potential drug target in various psychiatric disorders. The 5-HT3 receptor is a pentameric ligand-gated ion channel and belongs to the Cys-loop receptor family. In contrast to the immense heterogeneity characterizing other Cysloop receptors, native 5-HT3 receptors historically have been considered a much more homogenous receptor population. However, the recent discovery of additional 5-HT3 subunits and the dawning realization that central and peripheral 5-HT3 receptor populations might comprise several subtypes characterized by distinct functional properties has emphasized the complexity of human 5-HT3 receptor signaling. In this review potential implications of these findings and of the entirely new layer of interindividual diversity introduced to the 5-HT3 receptor system by genetic variations will be outlined.

Figure 1

The human 5-HT₃ receptor family. (a) The human 5-HT₃ subunits. 5-HT_3A: compared to the canonical 5-HT_3A, 5-HT_3AL has a 32-amino-acid-residue insertion into the extracellular loop between transmembrane regions 2 and 3, and 5-HT_3AT has a 57-residue insertion (followed by a stop codon) after transmembrane region 1. 5-HT_3B: the 5-HT_3B BT-1 isoform only differs from the canonical 5-HT_3B in five of the first six amino acid residues of its N-terminal domain, whereas the 5-HT_3B BT-2 isoform lacks the first 77 residues of this domain compared to the mature canonical 5-HT_3B protein. Neither BT-1 nor BT-2 is predicted to contain a signal peptide. The localization of the Y129 residue in 5-HT_3B is indicated. 5-HT_3D: The 5-HT3D(short) and 5-HT3D(long) isoforms possess N-terminal domains of 57 and 230 amino acid residues, respectively. 5-HT_3E: 5-HT_3Ea only differs from the 5-HT_3E in the first 22 amino acid residues of its N-terminal domain, whereas 5-HT_3Eb has a 15-amino acid residue deletion as well as a 26-amino acid residue insertion in its N-terminal domain compared to 5-HT_3E. GenBank accession numbers: D49394 (canonical 5-HT_3A), AJ003078 (5-HT_3AL), AJ003080 (5-HT_3AT), AF080582 (canonical 5-HT_3B), AF459285 (5-HT_3C), AJ437318 (5-HT3D(long)), AY159812 (5-HT3D(short)), AY159813 (5-HT_3E), DQ644022 (5-HT_3Ea) and EU165354 (5-HT_3Eb). (b) The heterogeneity of human 5-HT₃ receptors. Examples of ‘simple’ heteromers, ‘complex’ heteromers composed of more than two different subunits and 5-HT_3AB receptor heteromers characterized by different subunit arrangements and stoichiometries. For simplicity, the various isoforms of the different subunits are not included in this figure. Abbreviations: amino acids, aa; transmembrane 1, TM1.

Figure 2

Interindividual 5-HT₃ receptor diversity arising from genetic variation: the 5-HT_3B(Y129S) variant. (a) Distribution of individuals homozygous for the ‘WT’ and variant alleles (Y/Y and S/S, respectively) and heterozygous individuals (Y/S) in five major populations. The figure is based on NCBI's dbSNP build 127, submission numbers ss48404756 and ss23605381. CEPH, Centre d’Etude du Polymorphisme Humain. (b) The heteromeric 5-HT_3AB receptor complexes formed in individuals homozygous for the ‘WT’ and variant alleles (Y/Y and S/S, respectively) and in heterozygous individuals (Y/S). (c) 5-HT_3B(Y129S)-containing 5-HT_3AB receptors exhibit significantly slower deactivation (left) and desensitization (right) kinetics than WT 5-HT_3AB receptors. Traces are from whole-cell recordings on HEK293 cells transiently expressing the two receptors and are reproduced from Ref. [41] with permission [Copyright (2008) National Academy of Sciences, U.S.A.]

Figure 3

The roles of 5-HT₃ receptors in the neurocircuitry associated with emesis and the potential impact of the 5-HT_3B(Y129S) variant. (a) Serotonin is released from enterochromaffin (EC) cells in the intestinal mucosa as a result of different luminal stimuli, including chemotherapy and radiation treatment, and activates 5-HT₃ receptors (and other serotonin receptors) in abdominal vagal afferents. (b) Activation of abdominal vagal afferents stimulates neurons in the area postrema (AP) and nucleus tractus solitarius (NTS), the emetic center of the medulla oblongata of the hindbrain [7]. Carriers of the 5-HT_3B(Y129S) variant potentially could have altered signals coming from 5-HT_3AB receptors expressed in vagal afferent neurons, in nodose ganglia neurons (known to express 5-HT_3B) that innervate NTS and in the AP and NTS. Part (b) of the figure is inspired by a similar figure in Ref. [7].