Extracellular UTP stimulates electrogenic bicarbonate secretion across CFTR knockout gallbladder epithelium

Extracellular UTP stimulates electrogenic bicarbonate secretion across CFTR knockout gallbladder epithelium. Am J Physiol Gastrointest Liver Physiol 279: G132-G138, 2000.--The loss of cystic fibrosis transmembrane conductance regulator (CFTR)-mediated transepithelial HCO[MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] secretion contributes to the pathogenesis of pancreatic and biliary disease in cystic fibrosis (CF) patients. Recent studies have investigated [P2Y.sub.2] nucleotide receptor agonists, e.g., UTP, as a means to bypass the CFTR defect by stimulating [Ca.sup.2+]-activated Cl[sup.-] secretion. However, the value of this treatment in facilitating transepithelial [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] secretion is unknown. Gallbladder mucosae from CFTR knockout mice were used to isolate the [Ca.sup.2+]-dependent anion conductance during activation of luminal [P2Y.sub.2] receptors. In Ussing chamber studies, UTP stimulated a transient peak in short-circuit current ([I.sub.sc]) that declined to a stable plateau phase lasting 30-60 min. The plateau [I.sub.sc] after UTP was [Cl.sup.-] independent, HCO[MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] dependent, insensitive to bumetanide, and blocked by luminal DIDS. In pH stat studies, luminal UTP increased both [I.sub.sc] and serosal-to-mucosal HCO[MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] flux ([J.sup.s[right arrow]m]) during a 30-min period. Substitution of [Cl.sup.-] with gluconate in the luminal bath to inhibit [C1.sup.-]/HCO[MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]exchange did not prevent the increase in [J.sup.s[right arrow]m] and [I.sub.sc] during UTP. In contrast, luminal DIDS completely inhibited UTP-stimulated increases in [J.sup.s[right arrow]m and [I.sub.sc]. We conclude that [P2Y.sub.2] receptor activation results in a sustained (30-60 rain) increase in electrogenic HCO3[MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] secretion that is mediated via an intracellular [Ca.sup.2+]-dependent anion conductance in CF gallbladder. cystic fibrosis; biliary system; [P2Y.sub.2] receptor; nucleotide receptor; purinoceptor; chloride