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GPCR activation of CFTR through two independent phosphorylation pathways

Cystic Fibrosis Transmembrane conductance Regulator (CFTR) activation by PKA and PKC has been extensively studied, however its regulation by receptors is less well understood. To study signaling upstream of the kinases, we measured whole‐cell Cl‐currents in BHK cells cotransfected with GPCRs and CFTR. In cells expressing the M3 muscarinic acetylcholine receptor, the agonist carbachol (Cch) caused strong activation of CFTR through two pathways; the canonical PKA‐dependent mechanism and a second mechanism mechanism that involves tyrosine phosphorylation. The role of PKA was suggested by partial activation of a mutant lacking tyrosine residues that mediate stimulation by the tyrosine kinase c‐Src. The role of tyrosine kinases was suggested by the ability of Cch to stimulate 15SA CFTR, a mutant which lacks 15 potential PKA sites and is unresponsive to PKA stimulation, and also by the sensitivity of the Cch response to inhibitors of the tyrosine kinase c‐Src. The results suggest that CFTR phosphorylation by PKA and tyrosine kinases both contribute to CFTR regulation by GPCRs that are expressed at the apical membrane of intestinal and airway epithelia.