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J. Biol. Chem., Vol. 279, Issue 13, 12529-12534, March 26, 2004

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Protons Activate the -Subunit of the Epithelial Na⁺ Channel in Humans^*

Hisao Yamamura, Shinya Ugawa, Takashi Ueda, Masataka Nagao¶, and Shoichi Shimada

From the Department of Molecular Morphology and ^¶Department of Forensic Medical Science, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan

The amiloride-sensitive epithelial Na⁺ channel (ENaC) controls Na⁺ transport into cells and across epithelia. So far, four homologous subunits of mammalian ENaC have been isolated and are denoted as , , , and . ENaC can associate with and subunits and generate a constitutive current that is 2 orders of magnitude larger than that of homomeric ENaC. However, the distribution pattern of ENaC is not consistent with that of the and subunits. ENaC is expressed mainly in the brain in contrast to and subunits, which are expressed in non-neuronal tissues. To explain this discrepancy, we searched for novel functional properties of homomeric ENaC and investigated the detailed tissue distribution in humans. When human ENaC was expressed in Xenopus oocytes and Chinese hamster ovary cells, a reduction of extracellular pH activated this channel (half-maximal pH for an activation of 5.0), and the acid-induced current was abolished by amiloride. The most striking finding was that the desensitization of the acid-evoked current was much slower (by 10% 120 s later), dissociating from the kinetics of acid-sensing ion channels in the degenerin/epithelial Na⁺ channel family, which were rapidly desensitized during acidification. RNA dot-blot analyses showed that ENaC mRNA was widely distributed throughout the brain and was also expressed in the heart, kidney, and pancreas in humans. Northern blotting confirmed that ENaC was expressed in the cerebellum and the hippocampus. In conclusion, human ENaC activity is regulated by protons, indicating that it may contribute to the pH sensation and/or pH regulation in the human brain.

Received for publication, January 12, 2004

^* This investigation was supported by a grant-in-aid for scientific research from the Japan Society for the Promotion of Sciences (to H. Y. and S. S.). 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: Dept. of Molecular Morphology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi Mizuhocho Mizuhoku, Nagoya 467-8601, Japan. Tel.: 81-52-853-8126; Fax: 81-52-852-8887; E-mail: yamamura{at}med.nagoyacu.ac.jp.

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