Small molecule activator of the human epithelial sodium channel.
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.
Lu
Min
M
Senomyx, Inc., San Diego, California 92121, USA.
Echeverri
Fernando
F
Kalabat
Dalia
D
Laita
Bianca
B
Dahan
David S
DS
Smith
Raymond D
RD
Xu
Hong
H
Staszewski
Lena
L
Yamamoto
Jeff
J
Ling
Jing
J
Hwang
Nancy
N
Kimmich
Rachel
R
Li
Peter
P
Patron
Erika
E
Keung
Walter
W
Patron
Andrew
A
Moyer
Bryan D
BD
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
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