General anesthetic action on 5-HT3 receptors: Influence of subunit composition

Abstract The 5-hydroxytryptamine (serotonin) type 3 (5-HT 3 ) receptor is one member of an anesthetic-sensitive superfamily of Cys-loop ligand-gated ion channels that is thought to be an important modulator of post-operative nausea and vomiting. Electrophysiological techniques were used to define and compare the actions of volatile and alcohol anesthetics on homomeric 5-HT 3A and heteromeric 5-HT 3AB receptors. We found that 5-HT 3AB receptors were significantly less sensitive than 5-HT 3A receptors to anesthetic-induced current potentiation by physically small anesthetics, but the degree of current inhibition induced by large anesthetics was similar in both receptor subtypes. We then used dopamine (DA), an inefficacious (i.e. partial) agonist of the 5-HT 3 receptor, to determine whether anesthetic-induced effects were due to changes in agonist affinity or channel gating. The small anesthetics chloroform and halothane elicited dramatic increases in DA-evoked currents at all concentrations of DA for the 5-HT 3A receptor, but only modest increases in DA-evoked currents were elicited for the 5-HT 3AB receptor. Neither anesthetic had a significant effect on the EC 50 of the DA concentration–response relationship. These results suggest that small anesthetics potentiate agonist-evoked currents for the 5-HT 3 receptor by enhancing channel gating, and not by increasing agonist affinity of the receptor.