title: Neuronal cGMP kinase I is essential for stimulation of duodenal bicarbonate secretion by luminal acid.
abstract: Brief contact of the duodenal mucosa with luminal acid elicits a long-lasting bicarbonate (HCO(3)(-)) secretory response, which is believed to be the primary protective mechanism against mucosal damage. Here, we show that cGMP-dependent protein kinase type I-knockout (cGKI(-/-)) mice are unable to respond to a physiological H(+) stimulus with a HCO(3)(-) secretory response and spontaneously develop duodenal ulcerations. Smooth muscle-selective cGKI knock-in rescued the motility disturbance but not the defective HCO(3)(-) secretion. Proton-induced HCO(3)(-) secretion was not attenuated by selective inactivation of the cGKI gene in interstitial cells of Cajal or in enterocytes, but was abolished by inactivation of cGKI in neurons (ncGKI(-/-)). cGKI was expressed in the brainstem nucleus tractus solitarius that connects the afferent with the efferent N. vagus. Accordingly, truncation of the subdiaphragmal N. vagus significantly diminished proton-induced HCO(3)(-) secretion in wild-type mice, whereas stimulation of the subdiaphragmal N. vagus elicited a similar HCO(3)(-) secretory response in cGKI(-/-), ncGKI(-/-) and wild-type mice. These findings show that protection of the duodenum from acid injury requires neuronal cGKI.
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Anurag Kumar
authors.initials: AK
authors.lastname: Singh
authors.forename: Beate
authors.initials: B
authors.lastname: Spiessberger
authors.forename: Wen
authors.initials: W
authors.lastname: Zheng
authors.forename: Fang
authors.initials: F
authors.lastname: Xiao
authors.forename: Robert
authors.initials: R
authors.lastname: Lukowski
authors.forename: Jörg W
authors.initials: JW
authors.lastname: Wegener
authors.forename: Pascal
authors.initials: P
authors.lastname: Weinmeister
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
authors.forename: Sabine
authors.initials: S
authors.lastname: Klein
authors.forename: Michael
authors.initials: M
authors.lastname: Schemann
authors.forename: Dagmar
authors.initials: D
authors.lastname: Krueger
authors.forename: Ursula
authors.initials: U
authors.lastname: Seidler
authors.forename: Franz
authors.initials: F
authors.lastname: Hofmann
mesh_terms: D000143:Acids / Q000378:metabolism*; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004381:Duodenal Ulcer / Q000378:metabolism / Q000473:pathology; D004386:Duodenum / Q000033:anatomy & histology / Q000378:metabolism*; D056885:Interstitial Cells of Cajal / Q000166:cytology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000201:enzymology*; D017552:Solitary Nucleus / Q000166:cytology / Q000378:metabolism; D014628:Vagotomy; D014630:Vagus Nerve / Q000378:metabolism
chemical_list: D000143:Acids; D001639:Bicarbonates; D005576:Colforsin; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569720:Prkg1 protein, mouse