Figure 3. Myocardial cell ultrastructure creates close associations between CaMKII targets important for membrane excitability and intracellular Ca²⁺ homeostasis.

Activated CaMKII enhances cellular Ca²⁺ entry by catalyzing phosphorylation of voltage-gated Ca²⁺ channels (mostly Ca_V1.2 in ventricle) and ryanodine receptor (RyR2) Ca²⁺ release channels. Ca_V1.2 and RyR2 are brought into close association (~10 nm) by Ca_V1.2 enrichment on T-tubular sarcolemmal invaginations. CaMKII phosphorylation of voltage-gated Na⁺ channels (mostly Na_V1.5 in ventricle) increases subsarcolemmal Na⁺ concentration that disadvantages the electrochemical driving force for Ca²⁺ extrusion from the cell by the Na⁺/Ca²⁺ exchanger (NCX), leading to increased intracellular Ca²⁺ concentration.