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Subunit-dependent modulation of the 5-hydroxytryptamine type 3 receptor open-close equilibrium by n-alcohols.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2007 Jun; Vol. 321 (3), pp. 1069-74. Date of Electronic Publication: 2007 Mar 07. - Publication Year :
- 2007
-
Abstract
- 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.
- Subjects :
- 1-Butanol pharmacology
1-Octanol pharmacology
1-Propanol pharmacology
Animals
Binding, Competitive
Dopamine pharmacology
Dose-Response Relationship, Drug
Drug Synergism
Electrophysiology
Ethanol pharmacology
Female
Gene Expression
Hexanols pharmacology
Humans
Ion Channel Gating physiology
Oocytes drug effects
Oocytes metabolism
Oocytes physiology
RNA, Messenger genetics
Receptors, Serotonin genetics
Receptors, Serotonin, 5-HT3 genetics
Receptors, Serotonin, 5-HT3 physiology
Serotonin pharmacology
Xenopus laevis
Fatty Alcohols pharmacology
Ion Channel Gating drug effects
Receptors, Serotonin physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0022-3565
- Volume :
- 321
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 17360702
- Full Text :
- https://doi.org/10.1124/jpet.106.118752