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

The 5-hydroxytryptamine (serotonin) type 3 (5-HT3) 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-HT3A and heteromeric 5-HT3AB receptors. We found that 5-HT3AB receptors were significantly less sensitive than 5-HT3A 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-HT3 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-HT3A receptor, but only modest increases in DA-evoked currents were elicited for the 5-HT3AB receptor. Neither anesthetic had a significant effect on the EC50 of the DA concentration-response relationship. These results suggest that small anesthetics potentiate agonist-evoked currents for the 5-HT3 receptor by enhancing channel gating, and not by increasing agonist affinity of the receptor.