The Journal of Neurophysiology Vol. 85 No. 5 May 2001, pp. 2030-2038
Copyright ©2001 by the American Physiological Society

Positive Allosteric Modulators of AMPA Receptors Reduce Proton-Induced Receptor Desensitization in Rat Hippocampal Neurons

 ¹Departments of Physiology and Pharmacology and Anaesthesia, University of Toronto, Toronto M5S 1A8; and  ²Department of Chemistry and  ³Department of Pharmacology and Toxicology, Queens University, Kingston, Ontario K7L 3N6, Canada

Lei, Saobo, Beverley A. Orser, Gregory R. L. Thatcher, James N. Reynolds, and John F. MacDonald. Positive Allosteric Modulators of AMPA Receptors Reduce Proton-Induced Receptor Desensitization in Rat Hippocampal Neurons. J. Neurophysiol. 85: 2030-2038, 2001. Whole-cell or outside-out patch recordings were used to investigate the effects of protons and positive modulators of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on the desensitization of glutamate-evoked AMPA receptor currents in isolated hippocampal CA1 neurons. Protons inhibited glutamate-evoked currents (IC₅₀ of 6.2 pH units) but also enhanced the apparent rate and extent of AMPA receptor desensitization. The proton-induced enhancement of desensitization could not be attributed to a reduction in the rate of recovery from desensitization or to a change in the kinetics of deactivation. Non-stationary variance analysis indicated that protons reduced maximum open probability without changing the conductance of AMPA channels. The positive modulators of AMPA receptor desensitization, cyclothiazide and GT-21-005 (an organic nitrate), reduced the proton sensitivity of AMPA receptor desensitization, which suggests that they interact with protons to diminish desensitization. In contrast, the effects of wheat germ agglutinin and aniracetam on AMPA receptor desensitization were independent of pH. These results demonstrate that a reduction in the proton sensitivity of receptor desensitization contributes to the mechanism of action of some positive modulators of AMPA receptors.