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The aim of this study was to investigate the interplay between NO and H<jats:sub>2<\/jats:sub>S in colonic smooth muscle. In colonic smooth muscle from rabbit, mouse, and human, l-cysteine, substrate of cystathionine-\u03b3-lyase (CSE), or NaHS, an H<jats:sub>2<\/jats:sub>S donor, inhibited phosphodiesterase 5 (PDE5) activity and augmented the increase in cGMP levels, IP<jats:sub>3<\/jats:sub> receptor phosphorylation at Ser<jats:sup>1756<\/jats:sup> (measured as a proxy for PKG activation), and muscle relaxation in response to NO donor S-nitrosoglutathione (GSNO), suggesting augmentation of cGMP\/PKG pathway by H<jats:sub>2<\/jats:sub>S. The inhibitory effect of l-cysteine, but not NaHS, on PDE5 activity was blocked in cells transfected with CSE siRNA or treated with CSE inhibitor d,l-propargylglycine (dl-PPG), suggesting activation of CSE and generation of H<jats:sub>2<\/jats:sub>S in response to l-cysteine. H<jats:sub>2<\/jats:sub>S levels were increased in response to l-cysteine, and the effect of l-cysteine was augmented by GSNO in a cGMP-dependent protein kinase-sensitive manner, suggesting augmentation of CSE\/H<jats:sub>2<\/jats:sub>S by cGMP\/PKG pathway. As a result, GSNO-induced relaxation was inhibited by dl-PPG. In flat-sheet preparation of colon, l-cysteine augmented calcitonin gene-related peptide release in response to mucosal stimulation, and in intact segments, l-cysteine increased the velocity of pellet propulsion. These results demonstrate that in colonic smooth muscle, there is a novel interplay between NO and H<jats:sub>2<\/jats:sub>S. NO generates H<jats:sub>2<\/jats:sub>S via cGMP\/PKG pathway, and H<jats:sub>2<\/jats:sub>S, in turn, inhibits PDE5 activity and augments NO-induced cGMP levels. In the intact colon, H<jats:sub>2<\/jats:sub>S promotes colonic transit. <\/jats:p><jats:p> NEW &amp; NOTEWORTHY Hydrogen sulfide (H<jats:sub>2<\/jats:sub>S) and nitric oxide (NO) are important regulators of gastrointestinal motility. The studies herein provide the cross talk between NO and H<jats:sub>2<\/jats:sub>S signaling to mediate smooth muscle relaxation and colonic transit. H<jats:sub>2<\/jats:sub>S inhibits phosphodiesterase 5 activity to augment cGMP levels in response to NO, which, in turn, via cGMP\/PKG pathway, generates H<jats:sub>2<\/jats:sub>S. These studies suggest that interventions targeted at restoring NO and H<jats:sub>2<\/jats:sub>S homeostasis within the smooth muscle may provide novel therapeutic approaches to mitigate motility disorders. <\/jats:p>","DOI":"10.1152\/ajpgi.00161.2017","type":"journal-article","created":{"date-parts":[[2017,7,13]],"date-time":"2017-07-13T21:10:25Z","timestamp":1499980225000},"page":"G330-G341","source":"Crossref","is-referenced-by-count":27,"title":["Augmentation of cGMP\/PKG pathway and colonic motility by hydrogen sulfide"],"prefix":"10.1152","volume":"313","author":[{"given":"Ancy D.","family":"Nalli","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, Virginia Commonwealth University Program in Enteric Neuromuscular Sciences, Virginia Commonwealth University, Richmond, Virginia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sayak","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"Department of Physiology and 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