Figure 5 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..