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State-Dependent Changes in the Electrostatic Potential in the Pore of a GluR Channel

Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, New York 11794-5230

Correspondence: Address reprint requests to Dr. Alexander I. Sobolevsky, Dept. of Biochemistry and Molecular Biophysics, Columbia University, Rm. 513, Black Bldg., 650 W. 168th St., New York, NY 10032. Tel.: 212-305-4062; Fax: 212-305-8174; E-mail: as2642{at}columbia.edu.

The M2 loop and the M3 segment are the major pore-lining domains in the GluR channel. These domains determine ion permeation and channel block processes and are extensively involved in gating. To study the distribution of the membrane electric potential across the GluR channel pore, we recorded from -amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors containing M2 and M3 cysteine substitutions in the GluR-A subunit and measured the voltage dependence of the modification rate of these substituted cysteines by methanethiosulfonate reagents either in the presence or absence of glutamate. In the presence of glutamate, the voltage dependence became gradually stronger for positions located deeper in the pore suggesting that the electrostatic potential drops fairly uniformly across the pore in the open state. In contrast, in the absence of glutamate, the voltage dependence was biphasic. The difference in the electrostatic potential in the presence and absence of glutamate had an apparent maximum in the middle of the extracellular vestibule. We suggest that these state-dependent changes in the membrane electric potential reflect a reorientation of the dipoles of the M2 loop -helices toward and away from the center of the channel pore during gating.

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