Fig. 6.

nNOS S1412 phosphorylation promotes enteric neuron NO signaling during low frequency depolarization. High frequency EFS (Right) promotes Ca²⁺ channel opening, which increases NO production via Ca²⁺/CaM dependent nNOS activation (thick arrows). Low frequency EFS (Left) slightly depolarizes nitrergic neurons, which activates Akt to phosphorylate nNOS S1412 and increase NO production (thick arrows). This pathway is independent of classical Ca²⁺/CaM activation. Regardless of nNOS stimulation, NO relaxes smooth muscle via a common final pathway in enteric myocytes by increasing cGMP synthesis. Through unknown mechanisms, NO bioavailability regulates PDE5 expression to modulate NO responses in smooth muscle cells. Thick or thin black pathway lines denote major and minor mechanisms of NO production. Dotted line represents unknown mechanisms.