alexa Abstract | Selective Activation of Cystic Fibrosis Transmembrane Conductance Regulator Cl- and HCO3 - Conductances

JOP. Journal of the Pancreas
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Abstract

While cystic fibrosis transmembrane conductance regulator (CFTR) is well known to function as a Clchannel, some mutations in the channel protein causing cystic fibrosis (CF) disrupt another vital physiological function, HCO3 - transport. Pathological implications of derailed HCO3 - transport are clearly demonstrated by the pancreatic destruction that accompany certain mutations in CF. Despite the crucial role of HCO3 - in buffering pH, little is known about the relationship between cause of CF pathology and the molecular defects arising from specific mutations. Using electrophysiological techniques on basolaterally permeabilized preparations of microperfused native sweat ducts, we investigated whether: a) CFTR can act as a HCO3 - conductive channel, b) different conditions for stimulating CFTR can alter its selectivity to HCO3 - and, c) pancreatic insufficiency correlate with HCO3 - conductance in different CFTR mutations. We show that under some conditions stimulating CFTR can conduct HCO3 - . HCO3 - conductance in the apical plasma membranes of sweat duct appears to be mediated by CFTR and not by any other Clchannel because HCO3 - conductance is abolished when CFTR is: a) deactivated by removing cAMP and ATP, b) blocked by 1 mM DIDS (4,4'- diisothiocyanostilbene-2,2'-disulfonic acid) in the cytoplasmic bath and, c) absent in the plasma membranes of DF508 CF ducts. Further, the HCO3 - /Cl- selectivity of CFTR appears to be dependent on the conditions of stimulating CFTR. That is, CFTR activated by cAMP + ATP appears to conduct both HCO3 - and Cl- (with an estimated selectivity ratio of 0.2 to 0.5). However, we found that in the apparent complete absence of cAMP and ATP, cytoplasmic glutamate activates CFTR Cl- conductance without any HCO3 - conductance. Glutamate activated CFTR can be induced to conduct HCO3 - by the addition of ATP without cAMP. The non-hydrolysable AMP-PNP (5'- adenylyl imidodiphosphate) cannot substitute for ATP in activating HCO3 - conductance. We also found that a heterozygous R117H/DF508 CFTR sweat duct retained significant HCO3 - conductance while a homozygous DF508 CFTR duct showed virtually no HCO3 - conductance. While we suspect that the conditions described here are not optimal for selectively activating CFTR Cl- and HCO3 - conductances, we surmise that CFTR may be subject to dramatic alterations in its conductance, at least to these two anions under distinctly different physiological conditions which require distinctly different physiological functions. That is physiologically, CFTR may exhibit Cl- conductance with and/or without HCO3 - conductance. We also surmise that the severity of the pathogenesis in CF is closely related to the phenotypic ability of a mutant CFTR to express a HCO3 - conductance.

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Author(s): MallaReddy M Reddy Paul M Quinton

 
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