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Acetylcholine Receptor Gating: Movement in the -Subunit Extracellular Domain

Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214

Correspondence to Anthony Auerbach: auerbach{at}buffalo.edu

Acetylcholine receptor channel gating is a brownian conformational cascade in which nanometer-sized domains (" blocks") move in staggering sequence to link an affinity change at the transmitter binding sites with a conductance change in the pore. In the -subunit, the first -block to move during channel opening is comprised of residues near the transmitter binding site and the second is comprised of residues near the base of the extracellular domain. We used the rate constants estimated from single-channel currents to infer the gating dynamics of Y127 and K145, in the inner and outer sheet of the ß-core of the -subunit. Y127 is at the boundary between the first and second blocks, at a subunit interface. Y127 mutations cause large changes in the gating equilibrium constant and with a characteristic -value ( = 0.77) that places this residue in the second -block. We also examined the effect on gating of mutations in neighboring residues I43 ( = 0.86), N39 (complex kinetics), I49 (no effect) and in residues that are homologous to Y127 on the , ß, and subunits (no effect). The extent to which Y127 gating motions are coupled to its neighbors was estimated by measuring the kinetic and equilibrium constants of constructs having mutations in Y127 (in both subunits) plus residues D97 or I43. The magnitude of the coupling between D97 and Y127 depended on the Y127 side chain and was small for both H (0.53 kcal/mol) and C (–0.37 kcal/mol) substitutions. The coupling across the single – subunit boundary was larger (0.84 kcal/mol). The -value for K145 (0.96) indicates that its gating motion is correlated temporally with the motions of residues in the first -block and is not synchronous with those of Y127. This suggests that the inner and outer sheets of the -subunit ß-core do not rotate as a rigid body.

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