Abstract
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-HT3AB receptors compared with homomeric 5-HT3A receptors. In this study, we used the highly inefficacious 5-HT3 receptor agonist dopamine to determine whether this difference between 5-HT3A and 5-HT3AB receptors reflects differential alcohol modulation of agonist binding affinity or channel gating efficacy. Human recombinant 5-HT3A and 5-HT3AB 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-HT3A than in 5-HT3AB 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-HT3B subunit in 5-HT3AB receptors significantly reduces the enhancement of gating efficacy by small alcohols without altering the inhibitory actions of large alcohols.
Footnotes
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This work was supported by Deutsche Forschungsgemeinschaft Grant RU1211/1-1 (to D.R.) and by National Institutes of Health Grant P01-GM58448 (to D.E.R.). Portions of this work were presented at the 2006 Annual Meeting of American Society of Anesthesiologists; 2006 Oct; Chicago, IL. American Society of Anesthesiologists, Park Ridge, IL.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.118752.
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ABBREVIATIONS: 5-HT, 5-hydroxytryptamine (serotonin); 5-HT3, 5-hydroxytryptamine type 3; DA, dopamine.
- Received December 18, 2006.
- Accepted March 2, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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