NOS activity requires homodimerization as well as three cosubstrates (L-arginine, NADPH and O2) and five cofactors or prosthetic groups (FAD, FMN, calmodulin, tetrahydrobiopterin and heme). Several distinct NOS isoforms have been described and been shown to represent the products of three distinct genes. These include two constitutive Ca2+/CaM-dependent forms of NOS, including NOS1 (also designated ncNOS) whose activity was first identified in neurons, and NOS3 (also designated ecNOS), first identified in endothelial cells.