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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 ??? but not ??? channels. To further elucidate this novel mechanism, we constructed mutants abolishing (?(?V348) and ?(H233R)) or augmenting (?(Y458A) and ?(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 (?(S520C)) and plasmin proteolytically cleaved channels. Our data suggest that elimination of self-inhibition of ??? ENaC may be a novel mechanism for CPT-cGMP to stimulate salt reabsorption in human lungs.

SUBMITTER: Han DY 

PROVIDER: S-EPMC3262684 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphate-Na stimulates human alveolar fluid clearance by releasing external Na+ self-inhibition of epithelial Na+ channels.

Han Dong-Yun DY   Nie Hong-Guang HG   Su Xue-Feng XF   Shi Xue-Mei XM   Bhattarai Deepa D   Zhao Meimi M   Zhao Run-Zhen RZ   Landers Katlin K   Tang Hua H   Zhang Lin L   Ji Hong-Long HL  

American journal of respiratory cell and molecular biology 20110511 5


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-i  ...[more]

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