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.