Subunit-Dependent Modulation of the 5-Hydroxytryptamine Type 3 Receptor Open-Close Equilibrium by n-Alcohols
Copyright policy )Subunit-Dependent Modulation of the 5-Hydroxytryptamine Type 3 Receptor Open-Close Equilibrium by n-Alcohols
5-Hydroxytryptamine (5-HT, serotonin) type 3 (5-HT(3)) receptors belong to the alcohol-sensitive superfamily of Cys-loop ligand-gated 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 voltage-clamp 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.
Dose-Response Relationship, Drug, Ethanol, Dopamine, Gene Expression, Drug Synergism, 1-Propanol, 1-Octanol, Binding, Competitive, Electrophysiology, 1-Butanol, Receptors, Serotonin, Oocytes, Animals, Humans, Female, RNA, Messenger, Fatty Alcohols, Receptors, Serotonin, 5-HT3, Hexanols, Ion Channel Gating
Dose-Response Relationship, Drug, Ethanol, Dopamine, Gene Expression, Drug Synergism, 1-Propanol, 1-Octanol, Binding, Competitive, Electrophysiology, 1-Butanol, Receptors, Serotonin, Oocytes, Animals, Humans, Female, RNA, Messenger, Fatty Alcohols, Receptors, Serotonin, 5-HT3, Hexanols, Ion Channel Gating
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