Cystic fibrosis transmembrane conductance regulator currents in guinea pig pancreatic duct cells: inhibition by bicarbonate ions.
OBJECTIVE
Cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channels play an important role in HCO(3)(-) secretion by pancreatic duct cells (PDCs). Our aims were to characterize the CFTR conductance of guinea pig PDCs and to establish whether CFTR is regulated by HCO(3)(-).


METHODS
PDCs were isolated from small intralobular and interlobular ducts, and their Cl(- )conductance was studied using the whole-cell patch clamp technique.


RESULTS
Activation of a typical CFTR conductance by adenosine 3',5'-cyclic monophosphate (cAMP) was observed in 114 of 204 cells (56%). A larger (10-fold), time- and voltage-dependent Cl(-) conductance was activated in 39 of 204 cells (19%). Secretin had a similar effect. Coexpression of both conductances in the same cell was observed, and both conductances had similar anion selectivity and pharmacology. Extracellular HCO(3)(-) caused a dose-dependent inhibition of both currents (K(i), approximately 7 mmol/L), which was independent of intracellular and extracellular pH, and the PCO(2) and CO(3)(2-) content of the bathing solutions.


CONCLUSIONS
Two kinetically distinct Cl(-) conductances are activated by cAMP in guinea pig PDCs. Because these conductances are coexpressed and exhibit similar characteristics (anion selectivity, pharmacology, and HCO(3)(-) inhibition), we conclude that CFTR underlies them both. The inhibition of CFTR by HCO(3)(-) has implications for the current model of pancreatic ductal HCO(3)(-) secretion.
O'Reilly
C M
CM
Department of Physiological Sciences, University Medical School, Newcastle upon Tyne, England.
Winpenny
J P
JP
Argent
B E
BE
Gray
M A
MA
D000818:Animals; D000838:Anions / Q000493:pharmacokinetics; D001639:Bicarbonates / Q000378:metabolism*; D002245:Carbon Dioxide / Q000378:metabolism; D018118:Chloride Channels / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004553:Electric Conductivity; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D010183:Pancreatic Ducts / Q000737:chemistry / Q000378:metabolism*; D010189:Pancreatic Juice / Q000378:metabolism; D012633:Secretin / Q000494:pharmacology; D017693:Sodium Bicarbonate / Q000493:pharmacokinetics*
D000838:Anions; D001639:Bicarbonates; D018118:Chloride Channels; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012633:Secretin; D002245:Carbon Dioxide; D005576:Colforsin; D017693:Sodium Bicarbonate; D000242:Cyclic AMP