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J. Biol. Chem., Vol. 279, Issue 43, 44483-44489, October 22, 2004

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Capsazepine Is a Novel Activator of the Subunit of the Human Epithelial Na⁺ Channel^*

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) regulates Na⁺ homeostasis into cells and across epithelia. So far, four homologous subunits of mammalian ENaC have been isolated and are denoted as , , , and . The chemical agents acting on ENaC are, however, largely unknown, except for amiloride and benzamil as ENaC inhibitors. In particular, there are no agonists currently known that are selective for ENaC, which is mainly expressed in the brain. Here we demonstrate that capsazepine, a competitive antagonist for transient receptor potential vanilloid subfamily 1, potentiates the activity of human ENaC (hENaC) heteromultimer expressed in Xenopus oocytes. The inward currents at a holding potential of –60 mV in hENaC-expressing oocytes were markedly enhanced by the application of capsazepine (1 µM), and the capsazepine-induced current was mostly abolished by the addition of 100 µM amiloride. The stimulatory effects of capsazepine on the inward current were concentration-dependent with an EC₅₀ value of 8 µM. Neither the application of other vanilloid compounds (capsaicin, resiniferatoxin, and olvanil) nor a structurally related compound (dopamine) modulated the inward current. Although hENaC homomer was also significantly activated by capsazepine, unexpectedly, capsazepine had no effect on hENaC and caused a slight decrease on the hENaC current. In conclusion, capsazepine acts on ENaC and acts together with protons. Other vanilloids tested do not have any effect. These findings identify capsazepine as the first known chemical activator of ENaC.

Received for publication, August 4, 2004 , and in revised form, August 9, 2004.

^* This work 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.nagoya-cu.ac.jp.

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