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Vol. 54, Issue 1, 146-153, July 1998

Mutations at Lipid-Exposed Residues of the Acetylcholine Receptor Affect Its Gating Kinetics

Cecilia Bouzat, Ana M. Roccamo, Ingrid Garbus, and F. J. Barrantes

Instituto de Investigaciones Bioquímicas de Bahía Blanca, Universidad Nacional del Sur-Consejo Nacional de Investigaciones Científicas y Técnicas, 8000 Bahía Blanca, Argentina

The firmest candidate among the transmembrane portions of the nicotinic acetylcholine receptor (AChR) to be in contact with the lipid bilayer is the fourth segment, M4. To explore the contribution of alpha M4 amino acid residues of mouse AChR to channel gating, we combined site-directed mutagenesis with single-channel recordings. Two residues in alpha M4, Cys418 and Thr422, were found to significantly affect gating kinetics when replaced by alanine. AChRs containing alpha C418A and alpha T422A subunits form channels characterized by a 3- and 5-fold reduction in the mean open time, respectively, suggesting an increase in the closing rate due to the mutations. The calculated changes in the energy barrier for the channel closing process show unequal and coupled contributions of both positions to channel gating. Single-channel recordings of hybrid wild-type alpha /alpha T422A AChR show that the closing rate depends on the number of alpha  subunits mutated. Each substitution of threonine to alanine changes the energy barrier of the closing process by ~0.5 kcal/mol. Recordings of channels activated by high agonist concentration suggest that these mutations also impair channel opening. Both Cys418 and Thr422 have been postulated to be in contact with the lipid milieu and are highly conserved among species and subunits. Our results support the involvement of lipid-exposed residues in alpha M4 in AChR channel gating mechanism.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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