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J. Biol. Chem., Vol. 279, Issue 26, 26939-26947, June 25, 2004

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Degenerin Sites Mediate Proton Activation of -Epithelial Sodium Channel^*

Hong-Long Ji and Dale J. Benos

From the Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005

The -subunit of epithelial Na⁺ channels (ENaC) is predominately expressed in brain, heart, and pancreas. The amiloride sensitivity, Na⁺ conductance, and critical domains for gating are characterized as a cross between proton-activated Na⁺ channels and -ENaC. The hypothesis that external protons may activate human -ENaC was addressed by expressing -hENaC in Xenopus oocytes and evaluating proton-activated current with the two-electrode voltage clamp technique. Our results showed that protons transiently evoked a Na⁺ current with an EC₅₀ of pH 6 overlapped on the basal current of -hENaC. Proton-activated current was not observed in uninjected oocytes. Studies on gating kinetics revealed that activation, desensitization, and recovery times of proton-activated Na⁺ current were 3.8 ± 0.5 s, 253 ± 9.5 s, and 10 ± 3.6 s, respectively (n = 4–12). Alkali metal cation selectivity of the proton-activated current was identical to that of the basal current of -hENaC. The metabolic acids, lactate, pyruvate, and formate, modified the proton-activated current, as did hypo-osmotic stress. EDTA, hypo-osmolarity, and lactate enhanced proton activation synergistically. Our results suggest that -hENaC subunit is essential for proton-activated current and -subunit may potentially regulate the response of -hENaC to protons. We have concluded that -hENaC is a proton-activated cation channel whose closing gate can be regulated by a proton-induced conformational change. Proton-sensitivity of -hENaC may be an important mechanism for integrating external ischemic signals in inflamed and hypoxic tissues.

Received for publication, February 2, 2004 , and in revised form, April 14, 2004.

^* This work was supported by National Institutes of Health Grants DK37206 and DK56095. 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.

To whom correspondence should be addressed: 1918 University Blvd., 844 MCLM, Birmingham, AL 35294-0005. Tel.: 205-934-3758; Fax: 205-934-1445; E-mail: ji{at}physiology.uab.edu.

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