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NEUROPHARMACOLOGY

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

Department of Anesthesia and Critical Care, University Hospital Giessen-Marburg GmbH, Marburg, Germany (D.R., H.W., A.S.); Institute of Physiology and Pathophysiology, Division of Neuroendocrinology and Neurodynamics, Marburg University, Marburg, Germany (B.M.); and Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts (D.E.R.)

5-Hydroxytryptamine (5-HT, serotonin) type 3 (5-HT₃) 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-HT₃ 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-HT₃ 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 EC₅₀ 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.

Address correspondence to: Dr. Dirk Rüsch, Department of Anesthesia and Critical Care, University Hospital Giessen-Marburg GmbH, Marburg Campus, Baldingerstrasse, 35033 Marburg, Germany. E-mail: ruesch{at}staff.uni-marburg.de