Transmitter‐Gated Channels

Abstract

Overview: The 5-HT 3 receptor [nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-hydroxytryptamine (serotonin) receptors (Hoyer et al., 1994)] is a transmitter-gated ion channel of the Cys-loop family that includes the nicotinic acetylcholine, GABA A and strychninesensitive glycine receptors. The receptor exists as a pentamer of 4TM subunits that form an intrinsic cation selective channel. Five human 5-HT 3 receptor subunits have been cloned and homo-oligomeric assemblies of 5-HT 3A and hetero-oligomeric assemblies of 5-HT 3A and 5-HT 3B subunits have been characterised in detail. The recently described 5-HT 3C (ENSG00000178084), 5-HT 3D (ENSG00000186090) and 5-HT 3E (ENSG00000186038) subunits (Karnovsky et al., 2003;Niesler et al., 2003), like the 5-HT 3B subunit, do not form functional homomers, but are reported to assemble with the 5-HT 3A subunit to influence its functional expression rather than pharmacological profile (Niesler et al., 2007). The hetero-oligomeric 5-HT 3A /5-HT 3B receptor has been reported to contain two copies of the 5-HT 3A subunit and three copies of the 5-HT 3B subunit in the order B-B-A-B-A (Barrera et al., 2005). The 5-HT 3B subunit imparts distinctive biophysical properties upon hetero-oligomeric 5-HT 3A /5-HT 3B versus homo-oligomeric 5-HT 3A recombinant receptors (Davies et al., 1999;Dubin et al., 1999;Hanna et al., 2000;Kelley et al., 2003;Stewart et al., 2003; Peters et al., 2005), but generally has little effect upon the apparent affinity of agonists, or the affinity of antagonists (Brady et al., 2001; but see Dubin et al., 1999). However, 5-HT 3A and 5-HT 3A /5-HT 3B receptors differ in their allosteric regulation by some general anaesthetic agents and small alcohols (Solt et al., 2005;Rüsch et al., 2007). The potential diversity of 5-HT 3 receptors is increased by alternatively spliced variants of the 5-HT 3A subunit (Hope et al., 1993;Bruss et al., 2000), and tissue-specific preferences for different transcription start sites in the HTR3B gene, which could result in three different 5-HT 3B subunit N-termini (Tzvetkov et al., 2007). To date, inclusion of the 5-HT 3A subunit appears imperative for 5-HT 3 receptor function.Quantitative data in the table refer to homo-oligomeric assemblies of the human 5-HT 3A subunit, or the receptor native to human tissues. Notably, most ligands display significantly reduced affinities at the guinea-pig 5-HT 3 receptor in comparison with other species. In addition to the agents listed in the table, native and recombinant 5-HT 3 receptors are subject to allosteric modulation by extracellular divalent cations, alcohols, several general anaesthetics and 5-hydroxy-and halide-substituted indoles (see reviews by Parker et al., 1996; Lovinger, 1999; Lummis, 2006, 2007).

Bicuculline-Sensitive Primary Afferent Depolarization Remains after Greatly Restricting Synaptic Transmission in the Mammalian Spinal Cord

“…Large-diameter afferents preferentially express the vesicular ACh transporter as well as acetylcholinesterase (Willis and Coggeshall, 1991;Tata et al, 2004;Bellier and Kimura, 2007). Primary afferents also contain bicuculline-sensitive ␣9 and ␣10 nicotinic ACh receptor subunits (Rothlin et al, 1999;Lips et al, 2002;Alexander et al, 2007) and preliminary results demonstrate reduction in DRP amplitude by nicotinic receptor antagonists with reported actions on ␣9 receptors (Hochman et al, 2010).…”