Subunit-Dependent Modulation of the 5-Hydroxytryptamine Type 3 Receptor Open-Close Equilibrium by n-Alcohols

Abstract

5-Hydroxytryptamine (5-HT, serotonin) type 3 (5-HT 3 ) receptors belong to the alcohol-sensitive superfamily of Cys-loop ligandgated ion channels, and they are thought to play an important role in alcoholism. Alcohols with small molecular volumes increase the amplitude of currents evoked by low 5-HT concentrations and shift the 5-HT concentration-response curve for 5-HT 3 receptor activation leftward, indicative of increased receptor sensitivity to agonist. This action is significantly smaller when currents are mediated by heteromeric 5-HT 3AB receptors compared with homomeric 5-HT 3A receptors. In this study, we used the highly inefficacious 5-HT 3 receptor agonist dopamine to determine whether this difference between 5-HT 3A and 5-HT 3AB receptors reflects differential alcohol modulation of agonist binding affinity or channel gating efficacy. Human recombinant 5-HT 3A and 5-HT 3AB receptors were expressed in Xenopus oocytes, and currents were measured in the absence and presence of alcohols using the two-electrode voltageclamp technique. Modulation by alcohols of peak currents elicited by maximally activating concentrations of dopamine was alcohol concentration-dependent. Potentiation by smaller alcohols was consistently significantly greater in 5-HT 3A than in 5-HT 3AB receptors, whereas inhibition by larger alcohols was not. A representative small (butanol) and large (octanol) alcohol failed to alter the EC 50 value for channel activation by dopamine. We conclude that the presence of the 5-HT 3B subunit in 5-HT 3AB receptors significantly reduces the enhancement of gating efficacy by small alcohols without altering the inhibitory actions of large alcohols.The 5-hydroxytryptamine (5-HT, serotonin) type 3 (5-HT 3 ) receptor is a pentameric cation channel belonging to the anesthetic-sensitive superfamily of Cys-loop ligand-gated ion channels that also includes the nicotinic acetylcholine receptor, GABA A receptor, and glycine receptor. Five human 5-HT 3 receptor subunits (A, B, C, D, and E) have been cloned (Maricq et al., 1991;Davies et al., 1999;Dubin et al., 1999;Karnovsky et al., 2003;Niesler et al., 2003). However, only the 5-HT 3A and the 5-HT 3B subunit have been shown to form functional receptors. Furthermore, whereas 5-HT 3A subunits can form functional homomeric receptors, 5-HT 3B subunits must combine with 5-HT 3A subunits to form functional heteromeric receptors. In general, 5-HT 3A receptors are more widely distributed in the central nervous system than 5-HT 3AB receptors. Expression of the latter has been detected by some (Davies et al., 1999;Dubin et al., 1999;Monk et al., 2001;Reeves and Lummis, 2006) but not all (Morales and Wang, 2002) studies in specific areas of the mammalian brain with strongest expression found in the amygdala and the hippocampus. 5-HT 3 receptors are thought to play an important role in alcoholism (McBride et al., 2004), and clinical studies have shown that 5-HT 3 receptor antagonists are effective at reducing the craving for alcohol, the number of drinking episo...

Activation and modulation of recombinantly expressed serotonin receptor type 3A by terpenes and pungent substances

“…Therefore, we tested whether aliphatic n-alcohols also block 5-HT-induced currents. For some of these n-alcohols, a blocking action on dopamine but not on 5-HT-evoked currents has already been described [19]. Among the aliphatic n-alcohols, 1-octanol was the most effective at reducing currents by 94 ± 2 %, followed by longer chained 1-decanol (77 ± 3 %).…”

Structural Basis of Alcohol Inhibition of the Pentameric Ligand-Gated Ion Channel ELIC

“…n -Alcohols enhance functions of GlyRs (Mascia et al, 1996a; Perkins et al, 2010) and most GABA A Rs (Mihic et al, 1997; Nakahiro et al, 1996), but suppress others such as α7nAChR and ρ1GABA A R (Cardoso et al, 1999; Covernton and Connolly, 1997; Mihic and Harris, 1996; Oz et al, 2005; Yu et al, 1996). Functional enhancement or suppression may depend on the molecular volume of alcohols and the receptor binding sites (Bradley et al, 1984; Cardoso et al, 1999; Nagata et al, 1996; Rusch et al, 2007; Stevens et al, 2005a; Stevens et al, 2005b; Wick et al, 1998). The phenomenon of alcohol cutoff (Pringle et al, 1981) has been observed for loss of righting reflex in tadpoles (Alifimoff et al, 1989) and also been observed in functional modulation of pLGICs (Dildy-Mayfield et al, 1996; Mascia et al, 1996a; Wick et al, 1998; Zuo et al, 2001).…”

The Concise Guide to PHARMACOLOGY 2013/14: Ligand‐Gated Ion Channels

“…The 5-HT 3 B subunit imparts distinctive biophysical properties upon hetero-oligomeric 5-HT 3 AB versus homo-oligomeric 5-HT 3 A recombinant receptors 8,10,11,19,23,37,40, influences the potency of channel blockers, but generally has only a modest effect upon the apparent affinity of agonists, or the affinity of antagonists (5, but see 7,9,10) which may be explained by the orthosteric binding site residing at an interface formed between 5-HT 3 A subunits 25,47. However, 5-HT 3 A and 5-HT 3 AB receptors differ in their allosteric regulation by some general anaesthetic agents, small alcohols and indoles 17,38,39. The potential diversity of 5-HT 3 receptors is increased by alternative splicing of the genes HTR3A and E 6,14,31,33,34.…”