Nitrergic relaxation in the gastrointestinal tract of mice with cell-specific deletion of NO-sensitive guanylyl cyclase

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NO-sensitive guanylyl cyclase (NO-GC) catalyzes the generation of the intracellular second messenger cGMP. The enzyme plays a key role within NO/cGMP signalling. Being the most important receptor for the signal molecule nitric oxide, NO-GC participates in the regulation of many different physiological functions.We have generated mice which lack NO-GC ubiquitously. These mice are hypertensive, suffer from gastrointestinal dysmotility and die prematurely. The exact identity of the cells/tissues responsible for the individual phenotypes remains to be resolved.The reduced GI motility in the general GCKO mice can be explained by the loss of nitrergic relaxation. The exact mechanism of nitrergic relaxation has not been investigated thoroughly. It is currently being heavily discussed in the field whether neuronally released NO acts to relax smooth muscle cells (SMC) directly (similar to the action of endothelial NO in the vascular system) or whether interstitial cells of Cajal (ICC) are interposed to mediate nitrergic relaxation. In addition, a third cell type called 'fibroblast-like cell' with high NO-GC expression has been identified.We have already generated KO mice in which NO-GC is deleted specifically in SMC or in ICC. Nitrergic relaxation of GI tissue is moderately affected in the two single knockouts. A double mutant carrying a deletion of NO-GC in both SMC and ICC shows strong reduction of GI motility and an almost total lack of nitrergic relaxation. In this project, we would like to generate mice that lack NO-GC in FLC; in addition, we will generate double and triple mutants. Organ bath experiments and measurements of membrane potential including inhibitory junction potentials will be performed. With the help of these mice lacking the NO receptor in the most important NO-GC expressing cells in the gut, we will investigate the interplay of these cells and identify the exact mechanism of nitrergic relaxation.