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Small Molecule Activator of the Human Epithelial Sodium Channel*

Min Lu,F. Echeverri,Dalia Kalabat,Bianca Laita,D. Dahan,Raymond D. Smith,Hong Xu,L. Staszewski,J. Yamamoto,Jing Ling,N. Hwang,R. Kimmich,Peter M. Li,Erika Patron,Walter Keung,A. Patron,B. Moyer

Published 2008 in Journal of Biological Chemistry

ABSTRACT

The epithelial sodium channel (ENaC), a heterotrimeric complex composed of α, β, and γ 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 αβG37Sγ 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.

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