QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.050542v1 306/2/595    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sessoms-Sikes, J. S. Articles by Machu, T. K. Search for Related Content PubMed PubMed Citation Articles by Sessoms-Sikes, J. S. Articles by Machu, T. K.

NEUROPHARMACOLOGY

A Mutation in Transmembrane Domain II of the 5-Hydroxytryptamine_3A Receptor Stabilizes Channel Opening and Alters Alcohol Modulatory Actions

Departments of Pharmacology (M.E.H., L-X.L., T.K.M.) and Anesthesiology (T.K.M.), Texas Tech University Health Sciences Center, Lubbock, Texas; and Department of Molecular Physiology and Biophysics (J.S.S-S., D.M.L.), Vanderbilt University School of Medicine, Nashville, Tennessee

Mutant 5-hydroxytryptamine (5-HT)_3A receptors, in which changes were made at Ile294, position 16', of the second transmembrane domain, were assessed for alterations in macroscopic response kinetics and modulation by alcohols. Function of heterologously expressed receptors was measured in Xenopus oocytes in the two-electrode voltage clamp configuration and in human embryonic kidney 293 cells using whole cell patch-clamp electrophysiological recordings with rapid drug application. Compared with the wild-type receptor, a decrease in the 5-HT EC₅₀ value in the Ile294Thr mutant was observed, whereas an increase in the 5-HT EC₅₀ value in the Ile294Leu mutant was measured. Ile294Thr receptors showed a marked reduction in the extent of desensitization. Ethanol and 2,2,2-trichloroethanol (TCEt) enhanced 5-HT-mediated currents in wild-type and Ile294Leu receptors, but inhibited or had little stimulatory effect in the Ile294Thr mutant. Kinetic analysis revealed that in the presence of TCEt, the slope of activation was unchanged in the Ile294Thr mutant and increased in the wild-type receptor. Alcohol cutoff was altered with wild-type = heptanol and Ile294Leu = hexanol. Kinetic changes in the Ile294Thr mutant that favor the open channel state, as well as reduction in the rate of channel activation in the presence of TCEt, likely underlie this mutant's altered response to n-chain alcohols.

Address correspondence to: Dr. Tina K. Machu, Dept. of Pharmacology, Texas Tech University Health Sciences Center, 3601 Fourth St., Lubbock, TX 79430. E-mail: tina.machu{at}ttuhsc.edu

This article has been cited by other articles:

				M. Wittmann, I. Peters, T. Schaaf, H. C. Wartenberg, S. Wirz, J. Nadstawek, B. W. Urban, and M. Barann The Effects of Morphine on Human 5-HT3A Receptors. Anesth. Analg., September 1, 2006; 103(3): 747 - 752. [Abstract] [Full Text] [PDF]

				J. J. Crowley, S. N. Treistman, and A. M. Dopico Distinct Structural Features of Phospholipids Differentially Determine Ethanol Sensitivity and Basal Function of BK Channels Mol. Pharmacol., July 1, 2005; 68(1): 4 - 10. [Abstract] [Full Text] [PDF]