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.
Rüsch
Dirk
D
Department of Anesthesia and Critical Care, University Hospital Giessen-Marburg GmbH, Marburg Campus, Baldingerstrasse, 35033 Marburg, Germany. ruesch@staff.uni-marburg.de
Musset
Boris
B
Wulf
Hinnerk
H
Schuster
Anika
A
Raines
Douglas E
DE
D020001:1-Butanol / Q000494:pharmacology; D020003:1-Octanol / Q000494:pharmacology; D000433:1-Propanol / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D004298:Dopamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004594:Electrophysiology; D000431:Ethanol / Q000494:pharmacology; D005233:Fatty Alcohols / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression; D000441:Hexanols / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D011985:Receptors, Serotonin / Q000235:genetics / Q000502:physiology*; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology; D014982:Xenopus laevis
D005233:Fatty Alcohols; C509409:HTR3A protein, human; C509410:HTR3B protein, human; D000441:Hexanols; D012333:RNA, Messenger; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin; D000431:Ethanol; C036260:1-hexanol; D020001:1-Butanol; D000433:1-Propanol; D020003:1-Octanol; D004298:Dopamine