title: 8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphate-Na stimulates human alveolar fluid clearance by releasing external Na+ self-inhibition of epithelial Na+ channels.
abstract: Salt absorption via alveolar epithelial Na(+) channels (ENaC) is a critical step for maintaining an airspace free of flooding. Previously, we found that 8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphate-Na (CPT-cGMP) activated native and heterologous ENaC. To investigate the potential pharmacological relevance, we applied this compound intratracheally to human lungs and found that ex vivo alveolar fluid clearance was increased significantly. Furthermore, this compound eliminated self-inhibition in human lung H441 cells and in oocytes expressing human αβγ but not δβγ channels. To further elucidate this novel mechanism, we constructed mutants abolishing (β(ΔV348) and γ(H233R)) or augmenting (α(Y458A) and γ(M432G)) self-inhibition. The mutants eliminating self-inhibition lost their responses to CPT-cGMP, whereas those enhancing self-inhibition facilitated the stimulatory effects of this compound. CPT-cGMP was unable to activate a high P(o) mutant (β(S520C)) and plasmin proteolytically cleaved channels. Our data suggest that elimination of self-inhibition of αβγ ENaC may be a novel mechanism for CPT-cGMP to stimulate salt reabsorption in human lungs.
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center at Tyler, USA.
authors.forename: Dong-Yun
authors.initials: DY
authors.lastname: Han
authors.forename: Hong-Guang
authors.initials: HG
authors.lastname: Nie
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Su
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Shi
authors.forename: Deepa
authors.initials: D
authors.lastname: Bhattarai
authors.forename: Meimi
authors.initials: M
authors.lastname: Zhao
authors.forename: Run-Zhen
authors.initials: RZ
authors.lastname: Zhao
authors.forename: Katlin
authors.initials: K
authors.lastname: Landers
authors.forename: Hua
authors.initials: H
authors.lastname: Tang
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Hong-Long
authors.initials: HL
authors.lastname: Ji
mesh_terms: D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D062708:Epithelial Sodium Channel Agonists; D053503:Epithelial Sodium Channels / Q000235:genetics; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*
chemical_list: C474799:CPT-cGMP; D062708:Epithelial Sodium Channel Agonists; D053503:Epithelial Sodium Channels; D012964:Sodium; D006152:Cyclic GMP