Figure 5.

nNOS S1412 phosphorylation augments cAMP‐dependent enteric relaxation. Forskolin (FSK) relaxes GI smooth muscle via nitrergic (NO‐dependent) and non‐nitrergic mechanisms. Left. A model for nitrergic FSK relaxation. FSK stimulates AC to synthesize cAMP, which activates PKA phosphorylation of nNOS S1412 in myenteric inhibitory neurons. Phosphorylation enhances nNOS activity, thereby increasing NO‐cGMP‐dependent relaxation in myocytes. Akt phosphorylation of eNOS facilitates basal NO release, but eNOS stimulation plays a small role in nitrergic FSK relaxation. Inset shows gut layers. Right. Contribution of nNOS, eNOS and other factors in FSK relaxation. Top. At low to moderate [FSK], nNOS activation is the primary relaxation mechanism in WT animals with a small contribution from eNOS. At high [FSK], relaxation is primarily non‐nitrergic and may involve AC‐independent effects of FSK. Bottom. nNOS^S1412A mutation abolishes most nitrergic FSK relaxation, but non‐phosphorylation dependent nNOS activation and possibly eNOS can still mediate nitrergic relaxation at low to moderate [FSK]