Figure 3.

Mutual regulation of nNOS and CaMKII in the nerve systems. Both CaMKII and nNOS are activated by CaM binding (Stimulated). CaMKII is either autophosphorylated at Thr286 or S-nitrosylated at Cys280/Cys289 and earns Ca²⁺ independent autonomous activity. KN-93 and KN-62 generally used as CaMKII inhibitors inhibit CaM binding of CaMKII and thereby autonomous activity of CaMKII is not inhibited by KN-93 and KN-62. nNOS-derived NO inhibits CaMKII activity and both Ca²⁺ dependent and Ca²⁺ independent autonomous activity via S-nitrosylation at Cys6 with ATP competitive fashion [39]. On the other hand, CaMKII phosphorylates at Ser847 of nNOS which decrease NO synthesis and increase superoxide (O₂^–) synthesis. O₂^– reacts with NO to form peroxynitrite which indicates neurotoxic effects with oxidation of DNA [67]. Peroxynitrite also works as a signal molecule when it induces expression of cytoprotective proteins such as heme oxygenase-1 (HO-1) [28]. Ca²⁺ signals orchestrate NO and superoxide and phosphorylation by interaction between CaMKII and nNOS in the central nervous system. This figure is an image of the postsynaptic hippocampal neuron where the mutual regulation of nNOS and CaMKII mainly exists.