Fig. 2.

Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) targets diverse intracellular substrates to regulate heart function. CaMKII targets critical sarcolemmal ion channels important for cell excitability, including voltage-gated Na⁺ channels (Na_v1.5), L-type Ca²⁺ channels (Ca_v1.2, α- and β-subunits), as well as repolarizing currents Kv4.3 (transient outward K⁺ current, I_to) and Kir2.1 (inwardly rectifying K⁺ current, I_K1). CaMKII also regulates sarcoplasmic reticulum (SR) Ca²⁺ release and reuptake via direct phosphorylation of ryanodine recptor 2 (RyR2) SR Ca²⁺ release channels and phospholamban (PLB). In the nucleus, CaMKII phosphorylates histone deacetylase 5 (HDAC5), a repressor of myocyte enhancer factor-2 (MEF2), to regulate transcription of hypertrophic gene program. SERCA2a, sarco(endo)plasmic reticulum Ca²⁺-ATPase 2a. Figure and legend are from Mohler and Hund (146), used with permission.