Received for publication December 27, 2004.
Revised July 19, 2005.
Accepted for publication July 20, 2005.

Icilin activates the -subunit of the human epithelial Na⁺ channel

Abstract

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 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.

Key words: Ion channel regulation, Sodium

This article has been cited by other articles:

				S. Haerteis, B. Krueger, C. Korbmacher, and R. Rauh The {delta}-Subunit of the Epithelial Sodium Channel (ENaC) Enhances Channel Activity and Alters Proteolytic ENaC Activation J. Biol. Chem., October 16, 2009; 284(42): 29024 - 29040. [Abstract] [Full Text] [PDF]

				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]