Type II protein kinase A regulates CFTR in airway, pancreatic, and intestinal cells.
The type of protein kinase A (PKA) responsible for cystic fibrosis transmembrane conductance regulator (CFTR) activation was determined with adenosine 3', 5'-cyclic monophosphate analogs capable of selectively activating type I or type II PKA. The type II-selective pair stimulated chloride efflux in airway, pancreatic, and colonic epithelial cells; the type I-selective pair only stimulated a calcium-dependent efflux in airway cells. The type II-selective analogs activated larger increases in CFTR-mediated current than did the type I-selective analogs. Measurement of soluble PKA activity demonstrated similar levels stimulated by type I- and type II-selective analogs, creating an apparent paradox regarding PKA activity and current generated. Also, addition of forskolin after the type I-selective analogs resulted in an increase in current; little increase was seen after the type II-selective analogs. Measurement of insoluble PKA activity stimulated by the analogs resolved this paradox. Type II-selective analogs stimulated three times as much insoluble PKA activity as the type I-selective pair, indicating that differential activation of PKA in cellular compartments is important in CFTR regulation.
Steagall
W K
WK
Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio 44106-4948, USA.
Kelley
T J
TJ
Marsick
R J
RJ
Drumm
M L
ML
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D007476:Ionophores / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D009761:Nystatin / Q000494:pharmacology; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C505032:CFTR protein, human; D007476:Ionophores; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D009761:Nystatin; D005576:Colforsin; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid