Nitric oxide synthase mechanism and calmodulin dependent activation

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Nitric oxide (NO) is an important endogenous messenger in a variety of physiological and pathophysiological processes. NO is synthesized by the three isoforms of an enzyme, nitric oxide synthase (NOS) that are in part controlled by the binding of calmodulin (CaM). CaM is the primary protein mediator of the calcium cation which is also an important endogenous secondary messenger. CaM undergoes calcium concentration dependent conformational changes that allow it to differentially bind and activate scores of target proteins including the three NOS isozymes and voltage-gated calcium channels (VGCCs). Exactly how CaM manages to bind and sometimes control the activity of such a large variety of proteins and enzymes is not fully understood. The long-term objectives of this research program are to further our understanding of: 1) the mechanism and control of NO synthesis by NOS; 2) the CaM-dependent activation of its numerous target proteins including NOS isozymes and VGCCs.