QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.104.010850v1 68/4/1142    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yamamura, H. Articles by Shimada, S. Search for Related Content PubMed PubMed Citation Articles by Yamamura, H. Articles by Shimada, S.

Icilin Activates the -Subunit of the Human Epithelial Na⁺ Channel

Departments of Molecular Morphology (H.Y., S.U., T.U., S.S.) and Forensic Medical Science (M.N.), Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan

The amiloride-sensitive epithelial Na⁺ channel (ENaC) regulates Na⁺ homeostasis in cells and across epithelia. Four homologous ENaC subunits (, , , and ) have been isolated in mammals. The chemical activators acting on ENaC, however, are largely unknown. More recently, we have found that capsazepine activates human ENaC (hENaC), which is mainly expressed in the brain. In addition, here we show that icilin, which is a tetrahydropyrimidine-2-one derivative unrelated structurally to capsazepine, markedly enhanced the activity of hENaC heteromultimer expressed in Xenopus laevis oocytes. The inward currents at a holding potential of -60 mV in hENaC-expressing oocytes were increased by the application of icilin in a concentration-dependent manner with an EC₅₀ value of 33 µM. The icilin-elicited current was mostly abolished by the addition of 100 µM amiloride or by the removal of external Na⁺. Homomeric hENaC was also significantly activated by icilin, whereas hENaC activity was not affected by icilin, and icilin caused a slight inhibition of the hENaC current. Furthermore, icilin acted together with protons or capsazepine on hENaC. These findings identify icilin as a novel chemical activator of ENaC, providing us with a lead compound for drug development in the degenerin/ENaC superfamily.

Address correspondence to: Dr. Hisao Yamamura, Department of Molecular Morphology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi Mizuhocho Mizuhoku, Nagoya 467-8601, Japan. E-mail: yamamura{at}med.nagoya-cu.ac.jp

This article has been cited by other articles:

				M. Lu, F. Echeverri, D. Kalabat, B. Laita, D. S. Dahan, R. D. Smith, H. Xu, L. Staszewski, J. Yamamoto, J. Ling, et al. Small Molecule Activator of the Human Epithelial Sodium Channel J. Biol. Chem., May 2, 2008; 283(18): 11981 - 11994. [Abstract] [Full Text] [PDF]

				H. Yamamura, S. Ugawa, T. Ueda, and S. Shimada Evans Blue Is a Specific Antagonist of the Human Epithelial Na+ Channel {delta}-Subunit J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 965 - 969. [Abstract] [Full Text] [PDF]