Positive allosteric modulators of AMPA receptors reduce proton-induced receptor desensitization in rat hippocampal neurons

Whole-cell or outside-out patch recordings were used to investigate the eff ects of protons and positive modulators of alpha -amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid (AMPA) receptors on the desensitization of glutam ate-evoked AMPA receptor currents in isolated hippocampal CA1 neurons. Prot ons inhibited glutamate-evoked currents (IC50 of 6.2 pH units) but also enh anced the apparent rate and extent of AMPA receptor desensitization. The pr oton-induced enhancement of desensitization could not be attributed to a re duction in the rate of recovery from desensitization or to a change in the kinetics of deactivation. Non-stationary variance analysis indicated that p rotons reduced maximum open probability without changing the conductance of AMPA channels. The positive modulators of AMPA receptor desensitization, c yclothiazide and GT-21-005 (an organic nitrate), reduced the proton sensiti vity of AMPA receptor desensitization, which suggests that they interact wi th protons to diminish desensitization. In contrast, the effects of wheat g erm agglutinin and aniracetam on AMPA receptor desensitization were indepen dent of pH. These results demonstrate that a reduction in the proton sensit ivity of receptor desensitization contributes to the mechanism of action of some positive modulators of AMPA receptors.