{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T04:25:33Z","timestamp":1775276733508,"version":"3.50.1"},"reference-count":72,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2020,2,15]],"date-time":"2020-02-15T00:00:00Z","timestamp":1581724800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["5T32HD007186\u201037"],"award-info":[{"award-number":["5T32HD007186\u201037"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>The enteric neurotransmitter nitric oxide (NO) regulates gastrointestinal motility by relaxing smooth muscle. Pharmacological cAMP induction also relaxes gastrointestinal smooth muscle, but it is uncertain whether cAMP augments or suppresses enteric NO signalling. In other organ systems, cAMP can increase neuronal NO production by stimulating protein kinase A (PKA) to phosphorylate neuronal NOS (nNOS) Serine\u20101412 (S1412). We hypothesized that cAMP also increases nNOS S1412 phosphorylation by PKA in enteric neurons to augment nitrergic relaxation of mouse ileum.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We measured contractile force and nNOS S1412 phosphorylation in ileal rings suspended in an organ bath. We used forskolin to induce cAMP\u2010dependent relaxation of wild type, nNOS<jats:sup>S1412A<\/jats:sup> knock\u2010in and nNOS\u03b1\u2010null ileal rings in the presence or absence of PKA, protein kinase B (Akt) and NOS inhibitors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Forskolin stimulated phosphorylation of nNOS S1412 in mouse ileum. Forskolin relaxed nNOS\u03b1\u2010null and nNOS<jats:sup>S1412A<\/jats:sup> ileal rings less than wild\u2010type ileal rings. PKA inhibition blocked forskolin\u2010induced nNOS phosphorylation and attenuated relaxation of wild type but not nNOS<jats:sup>S1412A<\/jats:sup> ileum. Akt inhibition did not alter nNOS phosphorylation with forskolin but did attenuate relaxation of wild type and nNOS<jats:sup>S1412A<\/jats:sup>. NOS inhibition with <jats:sc>L<\/jats:sc>\u2010NAME eliminated the effects of PKA and Akt inhibitors on relaxation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>PKA phosphorylation of nNOS S1412 augments forskolin\u2010induced nitrergic ileal relaxation. The relationship between cAMP\/PKA and NO is therefore synergistic in enteric nitrergic neurons. Because NO regulates gut motility, selective modulation of enteric neuronal cAMP synthesis may be useful for the treatment of gastrointestinal motility disorders.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15001","type":"journal-article","created":{"date-parts":[[2020,1,24]],"date-time":"2020-01-24T05:06:07Z","timestamp":1579842367000},"page":"2765-2778","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Protein kinase A facilitates relaxation of mouse ileum via phosphorylation of neuronal nitric oxide synthase"],"prefix":"10.1111","volume":"177","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6621-4656","authenticated-orcid":false,"given":"Damian D.","family":"Guerra","sequence":"first","affiliation":[{"name":"Division of Reproductive Sciences, Department of Obstetrics and Gynecology University of Colorado Anschutz Medical Campus  Aurora Colorado"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachael","family":"Bok","sequence":"additional","affiliation":[{"name":"Division of Reproductive Sciences, Department of Obstetrics and Gynecology University of Colorado Anschutz Medical Campus  Aurora Colorado"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7330-6284","authenticated-orcid":false,"given":"Ram\u00f3n A.","family":"Lorca","sequence":"additional","affiliation":[{"name":"Division of Reproductive Sciences, Department of Obstetrics and Gynecology University of Colorado Anschutz Medical Campus  Aurora Colorado"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6906-350X","authenticated-orcid":false,"given":"K. 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