Differential role of cyclic GMP-dependent protein kinase II in ion transport in murine small intestine and colon.
OBJECTIVE
The aim of this study was to determine the role of guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase (cGK) type II in intestinal fluid homeostasis under basal conditions and following exposure to cGMP-linked secretagogues, e.g., Escherichia coli heat-stable enterotoxin (STa) and guanylin.


METHODS
Fluid and ion transport was determined in different segments of the intestine of wild-type and cGK II-deficient mice by ligated loop assays in vivo, and by short-circuit current and isotope flux measurements in vitro.


RESULTS
Small intestinal fluid absorption in vivo was enhanced in cGK II-deficient mice under basal conditions and in the presence of STa. Furthermore, STa, guanylin, and 8-pCPT-cGMP stimulation of electrogenic anion secretion and inhibition of Na(+) absorption in vitro were markedly reduced in the small intestine from cGK II -/- mice but not in proximal colon. The type III phosphodiesterase inhibitor amrinone mimicked STa action in cGK II -/- mice, and also stimulated ion secretion in humans.


CONCLUSIONS
This study shows that the cGMP/cGK II pathway regulates fluid homeostasis in the small intestine under basal conditions and mediates STa effects by both increasing anion secretion and inhibiting Na(+) absorption. It also demonstrates the presence of a cGK II-independent pathway for STa/cGMP-provoked secretion predominantly in the colon, which possibly involves a cGMP-inhibitable phosphodiesterase and/or activation of the cAMP-dependent protein kinase pathway.
Vaandrager
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AB
Department of Biochemistry, Cardiovascular Research Institute COEUR, Medical Faculty, Erasmus University Rotterdam, Rotterdam, The Netherlands.
Bot
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AG
Ruth
P
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Pfeifer
A
A
Hofmann
F
F
De Jonge
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HR
D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D062967:Cyclic GMP-Dependent Protein Kinase Type II; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004768:Enterotoxins / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology; D029968:Escherichia coli Proteins; D005768:Gastrointestinal Hormones; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism*; D017136:Ion Transport / Q000187:drug effects; D051379:Mice; D045265:Natriuretic Peptides; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology
D001427:Bacterial Toxins; D004768:Enterotoxins; D020536:Enzyme Activators; D029968:Escherichia coli Proteins; D005768:Gastrointestinal Hormones; D045265:Natriuretic Peptides; D010455:Peptides; D013873:Thionucleotides; C034151:heat stable toxin (E coli); C072685:guanylin; C055656:8-((4-chlorophenyl)thio)cyclic-3',5'-GMP; D062967:Cyclic GMP-Dependent Protein Kinase Type II; D017869:Cyclic GMP-Dependent Protein Kinases; C569729:PRKG2 protein, human; C569730:Prkg2 protein, mouse; D006152:Cyclic GMP