title: Small molecule activator of the human epithelial sodium channel.
abstract: The epithelial sodium channel (ENaC), a heterotrimeric complex composed of alpha, beta, and gamma 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 beta subunit. hENaC activation by S3969 did not require cleavage by the furin protease, indicating that nonproteolyzed channels can be opened. Function of alphabetaG37Sgamma 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.
authors.affiliation: Senomyx, Inc., San Diego, California 92121, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Fernando
authors.initials: F
authors.lastname: Echeverri
authors.forename: Dalia
authors.initials: D
authors.lastname: Kalabat
authors.forename: Bianca
authors.initials: B
authors.lastname: Laita
authors.forename: David S
authors.initials: DS
authors.lastname: Dahan
authors.forename: Raymond D
authors.initials: RD
authors.lastname: Smith
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.forename: Lena
authors.initials: L
authors.lastname: Staszewski
authors.forename: Jeff
authors.initials: J
authors.lastname: Yamamoto
authors.forename: Jing
authors.initials: J
authors.lastname: Ling
authors.forename: Nancy
authors.initials: N
authors.lastname: Hwang
authors.forename: Rachel
authors.initials: R
authors.lastname: Kimmich
authors.forename: Peter
authors.initials: P
authors.lastname: Li
authors.forename: Erika
authors.initials: E
authors.lastname: Patron
authors.forename: Walter
authors.initials: W
authors.lastname: Keung
authors.forename: Andrew
authors.initials: A
authors.lastname: Patron
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Moyer
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D053503:Epithelial Sodium Channels / Q000737:chemistry / Q000378:metabolism*; D005110:Extracellular Space; D005260:Female; D045683:Furin / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects*; D051379:Mice; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D011546:Pseudohypoaldosteronism / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D014981:Xenopus
chemical_list: D053503:Epithelial Sodium Channels; D007211:Indoles; C578389:N-(2-hydroxyethyl)-4-methyl-2-(4-methyl-1H-indol-3-ylthio)pentanamide; D021122:Protein Subunits; D054852:Small Molecule Libraries; D000584:Amiloride; D045683:Furin