title: Pseudohalide anions reveal a novel extracellular site for potentiators to increase CFTR function.
abstract: OBJECTIVE
  There is great interest in the development of potentiator drugs to increase the activity of the cystic fibrosis transmembrane conductance regulator (CFTR) in cystic fibrosis. We tested the ability of several anions to potentiate CFTR activity by a novel mechanism.
  
  
  METHODS
  Patch clamp recordings were used to investigate the ability of extracellular pseudohalide anions (Co(CN)(6) (3-) , Co(NO(2) )(6) (3-) , Fe(CN)(6) (3-) , IrCl(6) (3-) , Fe(CN)(6) (4-) ) to increase the macroscopic conductance of mutant CFTR in intact cells via interactions with cytoplasmic blocking anions. Mutagenesis of CFTR was used to identify a possible molecular mechanism of action. Transepithelial short-circuit current recordings from human airway epithelial cells were used to determine effects on net anion secretion.
  
  
  RESULTS
  Extracellular pseudohalide anions were able to increase CFTR conductance in intact cells, as well as increase anion secretion in airway epithelial cells. This effect appears to reflect the interaction of these substances with a site on the extracellular face of the CFTR protein.
  
  
  CONCLUSIONS
  Our results identify pseudohalide anions as increasing CFTR function by a previously undescribed molecular mechanism that involves an interaction with an extracellular site on the CFTR protein. Future drugs could utilize this mechanism to increase CFTR activity in cystic fibrosis, possibly in conjunction with known intracellularly-active potentiators.
authors.affiliation: Department of Physiology & Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Man-Song
authors.initials: MS
authors.lastname: Li
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Cowley
authors.forename: Paul
authors.initials: P
authors.lastname: Linsdell
mesh_terms: D000818:Animals; D002460:Cell Line; D003035:Cobalt / Q000494:pharmacology*; D006224:Cricetinae; D003486:Cyanides / Q000494:pharmacology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology*; D006801:Humans; D007495:Iridium / Q000494:pharmacology*; D009154:Mutation; D017671:Platinum Compounds / Q000494:pharmacology*
chemical_list: D003486:Cyanides; D017671:Platinum Compounds; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C015509:hexanitritocobaltate(III); C010978:hexachloroiridic acid; D003035:Cobalt; D007495:Iridium