CaMKII

CaMKII (calcium/calmodulin-dependent protein kinase II) is a serine/threonine kinase that plays a central role in calcium signaling. It is highly expressed in the brain, particularly in the hippocampus, where it regulates synaptic strength and plasticity, and is also found in cardiac muscle and other tissues. Four genes encode the isoforms CaMKIIα, CaMKIIβ, CaMKIIγ, and CaMKIIδ, which assemble into a dodecameric holoenzyme composed of multiple subunits.

Structure and activation: Each subunit contains a catalytic domain, a regulatory segment, and an association domain. In the resting state, the regulatory segment blocks the catalytic site. Ca2+/calmodulin binding relieves this autoinhibition and activates the kinase. Autophosphorylation at Thr286 (in α/β; Thr287 in γ/δ) produces Ca2+-independent autonomous activity and helps sustain signaling after Ca2+ signals decay. Inhibitory phosphorylation at Thr305/306 reduces calmodulin sensitivity. The holoenzyme can further be regulated by interactions with binding partners and, in some cases, by oxidative modification of methionines, which can prolong activity.

Function and targets: In neurons, CaMKII phosphorylates substrates that regulate synaptic transmission, including AMPA-type glutamate receptors (for example, GluA1 Ser831) and NMDA receptor subunits (e.g., NR2B), promoting receptor trafficking to synapses and strengthening synaptic connections. CaMKII is highly enriched at postsynaptic densities and is activated by Ca2+ influx through NMDA receptors during synaptic activity, contributing to long-term potentiation and learning and memory. In the heart, CaMKII modulates excitation–contraction coupling by phosphorylating L-type calcium channels, ryanodine receptors, and other targets, influencing contractility and rhythm.

Clinical relevance: Dysregulation of CaMKII signaling has been implicated in neurodegenerative disease, ischemia, and cardiac remodeling. As a central mediator of Ca2+ signaling, it remains a focus of research for understanding synaptic plasticity and for potential therapeutic interventions aimed at modulating CaMKII activity.