PUB - Publikationen an der Universität Bielefeld

Brief contact of the duodenal mucosa with luminal acid elicits a long-lasting bicarbonate (HCO3-) secretory response, which is believed to be the primary protective mechanism against mucosal damage. Here, we show that cGMP-dependent protein kinase type I-knock-out (cGKI-/-) mice are unable to respond to a physiological H+ stimulus with a HCO3- secretory response and spontaneously develop duodenal ulcerations. Smooth muscle-selective cGKI knock-in rescued the motility disturbance but not the defective HCO3- secretion. Proton-induced HCO3- 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 HCO3- secretion in wild-type mice, whereas stimulation of the subdiaphragmal N. vagus elicited a similar HCO3- secretory response in cGKI-/-, ncGKI-/- and wild-type mice. These findings show that protection of the duodenum from acid injury requires neuronal cGKI.—Singh, A. K., Spieβberger, B., Zheng, W., Xiao, F., Lukowski, R., Wegener, J. W., Weinmeister, P., Saur, D., Klein, S., Schemann, M., Krueger, D., Seidler, U., Hofmann, F. Neuronal cGMP kinase I is essential for stimulation of duodenal bicarbonate secretion by luminal acid. FASEB J. 26, 1745-1754 (2012). www.fasebj.org