Nitric oxide synthase calmodulin role

The last phase of the excitotoxic cascade involves the activation of various biochemical pathways, among which phospholipases, proteases (in particular cal-pain), kinases and calmodulin-regulated enzymes such as nitric oxide synthase (NOS) play a prominent role. 

G. Role for Calmodulin in Controlling Electron Transfer in Nitric Oxide Synthase... 

Abu Soud, H. M., and Stuehr, D. J. (1993). Nitric oxide synthases reveal a role for calmodulin in controlling electron transfer. Proc. Nad. Acad. Set. U.S.A. 90, 10769-10772. 

Mayer, B., John, M., and Bohme, E. (1990). Purification of a Ca /calmodulin-dependent nitric oxide synthase from procine cerebellum. Cofactor-role of tetrahydrobiopterin. FEES Lett. 277, 215-219. 

The CNS contains a substantial amount of nitric oxide synthase (NOS), which is found within certain classes of neurons. This neuronal NOS is an enzyme activated by calcium-calmodulin, and activation of NMDA receptors, which increases intracellular calcium, results in the generation of nitric oxide. Although a physiologic role for nitric oxide has been clearly established for vascular smooth muscle, its role in synaptic transmission and synaptic plasticity remains controversial. Perhaps the strongest case for a role of nitric oxide in neuronal signaling in the CNS is for long-term depression of synaptic transmission in the cerebellum. 

FIGURE I Role for calmodulin (CaM) in triggering interdomain electron transfer to the nitric oxide synthase (NOS) heme iron. Electrons derived from NADPH can transfer only into the flavin centers of CaM-free neuronal NOS (A). CaM binding to NOS occurs in response to elevated Ca concentrations, and this enables electrons to transfer from the flavins to the heme iron. Heme iron reduction is associated with increased NADPH oxidation and results in (B) superoxide (O2) production in the absence of L-arginine or (C) nitric oxide (NO) synthesis in the presence of L-arginine. FAD, Flavin-adenine dinucleotide FMN, flavin mononucleotide. 

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