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J. Biol. Chem., Vol. 281, Issue 39, 29369-29378, September 29, 2006

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Modulation of Acid-sensing Ion Channel Currents, Acid-induced Increase of Intracellular Ca²⁺, and Acidosis-mediated Neuronal Injury by Intracellular pH^*

From the Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232

Acid-sensing ion channels (ASICs), activated by lowering extracellular pH (pH_o), play an important role in normal synaptic transmission in brain and in the pathology of brain ischemia. Like pH_o, intracellular pH (pH_i) changes dramatically in both physiological and pathological conditions. Although it is known that a drop in pH_o activates the ASICs, it is not clear whether alterations of pH_i have an effect on these channels. Here we demonstrate that the overall activities of ASICs, including channel activation, inactivation, and recovery from desensitization, are tightly regulated by pH_i. In cultured mouse cortical neurons, bath perfusion of the intracellular alkalizing agent quinine increased the amplitude of the ASIC current by 50%. In contrast, intracellular acidification by withdrawal of NH₄Cl or perfusion of propionate inhibited the current. Increasing pH buffering capacity in the pipette solution with 40 mM HEPES attenuated the effects of quinine and NH₄Cl. The effects of intracellular alkalizing/acidifying agents were mimicked by using intracellular solutions with pH directly buffered at high/low values. Increasing pH_i induced a shift in H⁺ dose-response curve toward less acidic pH but a shift in the steady state inactivation curve toward more acidic pH. In addition, alkalizing pH_i induced an increase in the recovery rate of ASICs from desensitization. Consistent with its effect on the ASIC current, changing pH_i has a significant influence on the acid-induced increase of intracellular Ca²⁺, membrane depolarization, and acidosis-mediated neuronal injury. Our findings suggest that changes in pH_i may play an important role in determining the overall function of ASICs in both physiological and pathological conditions.

Received for publication, May 30, 2006 , and in revised form, July 6, 2006.

^* This work was supported by research grants from the National Institutes of Health, the American Heart Association, and the Legacy Research Advisory Committee. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Robert S. Dow Neurobiology Laboratories, Legacy Clinical Research Center, 1225 NE 2nd Ave., Portland, OR 97232. Tel.: 503-413-2086; Fax: 503-413-5465; E-mail: zxiong{at}Downeurobiology.org.

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