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Papers In Press, published online ahead of print October 3, 2002
J. Biol. Chem, 10.1074/jbc.M207683200
Submitted on July 30, 2002
Revised on September 18, 2002
Accepted on October 3, 2002

Distinct molecular basis for differential sensitivity of the 5-HT3A receptor to Ethanol in the absence and presence of agonist

Li Zhang, Masako Hosoi, Misa Fukuzawa, Hui Sun, Robert R. Rawlings, and Forrest F. Weight

Laboratory of Molecular and Cellular Neurobiology, NIAAA, Rockville, MD 20852

Corresponding Author: lzhang{at}niaaa.nih.gov

Ethanol can potentiate serotonin type 3 (5-HT3) receptor-mediated responses in various neurons and in cells expressing 5-HT3A receptors. However, the molecular basis for alcohol modulation of 5-HT3 receptor function has not been determined. Here we report that point-mutations of the arginine at amino acid 222 in the N-terminal domain of the 5-HT3A receptor can alter the EC50 value of the 5-HT concentration-response curve. Some point-mutations at amino acid 222 resulted in spontaneous opening of the 5-HT3A receptor-channel and an inward current activated by ethanol in the absence of agonist. Among these mutant receptors, the amplitude of the current activated by ethanol in the absence of agonist was correlated with the amplitude of the current resulting from spontaneous channel openings, suggesting that the receptor’s sensitivity to ethanol in the absence of agonist is, at least in part, dependent on the preexisting conformational equilibrium of the receptor protein. On the other hand, point-mutations that conferred greater sensitivity to ethanol of agonist-activated responses were less sensitive or insensitive to ethanol in the absence of agonist. For these receptors, the magnitude of the potentiation of agonist-activated responses by ethanol was inversely correlated with the EC50 values of the 5-HT concentration-response curves, suggesting that these mutations may modulate ethanol sensitivity of the receptor by altering the EC50 value of the receptor. Thus, distinct molecular processes may determine the sensitivity of 5-HT3A receptors to ethanol in the absence and presence of agonist.


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