FIG. 4. Mechanism of the regulation of the phosphorylation state and catalytic activity of NOS. NMDA receptor activations increase intracellular Ca2+ levels which subsequently activate NOS and calcineurin via calmodulin. With excessive NMDA receptor stimulation, large quantities of NO are produced and adjacent neurons die. NOS catalytic activity is inhibited by protein kinase C (PKC)-mediated phosphorylation as well as by cAMP- and cGMP-dependent protein kinases and Ca2+/calmodulin-dependent protein kinase. Ca2+ entry activates calcineurin, which dephosphorylates and activates NOS. FK506, complexed to FKBP, binds to calcineurin and inhibits its phosphatase activity. This prevents the dephosphorylation of NOS, thus decreasing NOS catalytic activity. NO production is subsequently lowered, and adjacent neurons remain viable. (From ref. 19.)