General anesthetic-induced channel gating enhancement of 5-hydroxytryptamine type 3 receptors depends on receptor subunit composition

5-Hydroxytryptamine (serotonin) (5-HT) type 3 (5-HT(3)) receptors are members of an anesthetic-sensitive superfamily of Cys-loop ligand-gated ion channels that can be formed as homomeric 5-HT(3A) or heteromeric 5-HT(3AB) receptors. When the efficacious agonist 5-HT is used, the inhaled anesthetics halothane and chloroform (at clinically relevant concentrations) significantly reduce the agonist EC(50) for 5-HT(3A) receptors but not for 5-HT(3AB) receptors. In the present study, we used dopamine (DA), a highly inefficacious agonist for 5-HT(3) receptors, to determine whether the difference in sensitivity between 5-HT(3A) and 5-HT(3AB) receptors to the potentiating effects of halothane and chloroform is due to differential modulation of agonist affinity, channel gating, or both. Using the two-electrode voltage-clamp technique with 5-HT(3A) and 5-HT(3AB) receptors expressed in Xenopus oocytes, we found that chloroform and halothane enhanced currents evoked by receptor-saturating concentrations of DA for both receptor subtypes in a concentration-dependent manner but that the magnitude of enhancement was substantially greater for 5-HT(3A) receptors than for 5-HT(3AB) receptors. Isoflurane induced only a small enhancement of currents evoked by receptor-saturating concentrations of DA for 5-HT(3A) receptors and no enhancement for 5-HT(3AB) receptors. For both receptor subtypes, none of the three test anesthetics significantly altered the agonist EC(50) for DA, implying that these anesthetics do not affect agonist binding affinity. Our results show that chloroform, halothane, and (to a much lesser degree) isoflurane enhance channel gating for 5-HT(3A) receptors and that the incorporation of 5-HT(3B) subunits to produce heteromeric 5-HT(3AB) receptors markedly attenuates the ability of these anesthetics to enhance channel gating.