Vol. 61, Issue 2, 369-378, February 2002

Protons Enhance the Gating Kinetics of the 3/4 Neuronal Nicotinic Acetylcholine Receptor by Increasing Its Apparent Affinity to Agonists

Galya Abdrakhmanova, Julia Dorfman, Yingxian Xiao, and Martin Morad

Department of Pharmacology, Georgetown University School of Medicine, Washington DC

Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed in the nervous system. Although there is a vast literature on the molecular, structural and pharmacological properties of neuronal nAChR, little is known of their pH regulation. Here we report that rapid acidification (pH 6.0) enhances the current through the 3/4 recombinant nAChRs expressed stably in human embryonic kidney 293 cells and accelerates its activation kinetics without altering selectivity. Acidification also strongly accelerates the decay kinetics ("desensitization") of cytisine- and nicotine-evoked currents (pK_a ~6.1), but the effect is somewhat smaller with acetylcholine and carbachol (undetermined pK_a values), suggesting that protonation of the agonist contributes to the relaxation of the current. Transient increases of [H⁺]_o from pH 7.4 to 6.0, during the time course of decay of the current, enhances the current and accelerates its decay kinetics in a manner similar to reactivation of current by higher concentrations of agonists. We suggest that protons interact with multiple extracellular sites on 3/4 nAChRs, decreasing the effective EC₅₀ values of the agonist and accelerating gating kinetics, in part by promoting agonist-induced block. We speculate that corelease of protons with ACh from the secretory vesicles may induce rapid and reversible conformational changes in the slowly "desensitizing" 3/4 nAChRs, leading to accelerated signaling.