Activation of intestinal CFTR Cl- channel by heat-stable enterotoxin and guanylin via cAMP-dependent protein kinase.
Heat-stable enterotoxins (STa) produced by pathogenic bacteria induce profound salt and water secretion in the gut, leading to diarrhea. Recently, guanylin, an endogenous peptide with properties similar to STa, was identified. While STa and guanylin bind to the same receptor guanylyl cyclase and raise cell cGMP, the signaling mechanism distal to cGMP remains controversial. Here we show that STa, guanylin and cGMP each activate intestinal Cl- secretion, and that this is abolished by inhibitors of cAMP-dependent protein kinase (PKA), suggesting that PKA is a major mediator of this effect. These agents induce Cl- secretion only in cells expressing the wild-type CFTR, indicating that this molecule is the final common effector of the signaling pathway. The involvement of CFTR suggests a possible cystic fibrosis heterozygote advantage against STa-induced diarrhea.
Chao
A C
AC
Department of Molecular Pharmacology, Falk Cardiovascular Research Center, Digestive Disease Center, Stanford University School of Medicine, CA 94305-5246.
de Sauvage
F J
FJ
Dong
Y J
YJ
Wagner
J A
JA
Goeddel
D V
DV
Gardner
P
P
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology*; D002712:Chlorides / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003550:Cystic Fibrosis; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005768:Gastrointestinal Hormones; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D045265:Natriuretic Peptides; D010455:Peptides / Q000494:pharmacology*; D014162:Transfection
C505032:CFTR protein, human; D018118:Chloride Channels; D002712:Chlorides; D005768:Gastrointestinal Hormones; D008565:Membrane Proteins; D045265:Natriuretic Peptides; D010455:Peptides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C072685:guanylin; D017868:Cyclic AMP-Dependent Protein Kinases