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J. Biol. Chem., Vol. 283, Issue 18, 11981-11994, May 2, 2008

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Small Molecule Activator of the Human Epithelial Sodium Channel^*

From the Senomyx, Inc., San Diego, California 92121

The epithelial sodium channel (ENaC), a heterotrimeric complex composed of , β, and subunits, belongs to the ENaC/degenerin family of ion channels and forms the principal route for apical Na⁺ entry in many reabsorbing epithelia. Although high affinity ENaC blockers, including amiloride and derivatives, have been described, potent and specific small molecule ENaC activators have not been reported. Here we describe compound S3969 that fully and reversibly activates human ENaC (hENaC) in an amiloride-sensitive and dose-dependent manner in heterologous cells. Mechanistically, S3969 increases hENaC open probability through interactions requiring the extracellular domain of the β subunit. hENaC activation by S3969 did not require cleavage by the furin protease, indicating that nonproteolyzed channels can be opened. Function of βG37S hENaC, a channel defective in gating that leads to the salt-wasting disease pseudohypoaldosteronism type I, was rescued by S3969. Small molecule activation of hENaC may find application in alleviating human disease, including pseudohypoaldosteronism type I, hypotension, and neonatal respiratory distress syndrome, when improved Na⁺ flux across epithelial membranes is clinically desirable.

Received for publication, September 25, 2007 , and in revised form, March 5, 2008.

^* 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.

¹ To whom correspondence and requests for materials should be addressed: Senomyx, Inc., 4767 Nexus Centre Dr., San Diego, CA 92121. Tel.: 858-646-8327; Fax: 858-404-0752; E-mail: bryan.moyer{at}senomyx.com.

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