Calcium-calmodulin network. Ca2+-signaling is mediated through several Ca2+-binding proteins, including calmodulin (CaM) and protein kinase C (PKC). The activity of N-methyl-d-aspartate (NMDA) receptors or voltage-sensitive Ca2+ channels leads to an increase in intracellular Ca2+, which triggers a release of calmodulin that was previously bound to neuromodulin or neurogranin. Depending on Ca2+, CaM modulates the activity of several key signaling molecules that are crucial for synaptic plasticity including adenylyl cyclases (AC), protein kinases, calcineurin, nitric oxide synthase, Ca2+-channels, ATP-dependent Ca2+-pumps, and the CaM-dependent protein kinases (CaMKII). CaM has four Ca2+ binding sites and in the presence of CaM binding protein, it shows heterotropic positive cooperativity for Ca2+. This enables that CaM-regulated AC and cyclic nucleotide phosphodiesterases have different Ca2+-sensitivities, and that CaM-stimulated phosphatase calcineurin has greater sensitivity to Ca2+ than CaMKII.
Klipp and Liebermeister BMC Neuroscience 2006 7(Suppl 1):S10 doi:10.1186/1471-2202-7-S1-S10