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

Hisao Yamamura, Shinya Ugawa, Takashi Ueda, Masataka Nagao, Shoichi Shimada
2004 Journal of Biological Chemistry  
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
more » ... nly 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 ϳ10% 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. Four homologous epithelial Na ϩ channel (ENaC) 1 subunits (␣, ␤, ␥, and ␦), members of the degenerin/epithelial Na ϩ channel superfamily, have been cloned in mammals (1-5). There is an overall ϳ37% amino acid identity between the ␣, ␤, ␥, and ␦ subunits. The ␦ subunit of ENaC was originally described as mainly being expressed in the human brain (5). ENaC␦ can
doi:10.1074/jbc.m400274200 pmid:14726523 fatcat:tvsewamdqngnpdmwurn4kjm3hm