CAMK2D (calcium/calmodulin-dependent protein kinase II delta) is a serine/threonine kinase essential for regulating cardiac calcium homeostasis and excitation-contraction coupling 1. The protein phosphorylates key ion channel regulators including phospholamban to enhance sarcoplasmic reticulum calcium uptake, and directly targets the ryanodine receptor RYR2 and L-type calcium channels to control intracellular calcium dynamics 2. CAMK2D also regulates sodium and potassium channels, contributing to cardiac electrophysiology 3. In pathological contexts, CAMK2D gain-of-function variants promote dilated cardiomyopathy and heart failure through excessive calcium-dependent signaling and arrhythmogenic calcium release 4. CAMK2D is alternatively spliced, with the CaMKIIδA isoform specifically activating L-type calcium currents and promoting calcium overload; aberrant splicing toward this isoform occurs in disease states and contributes to arrhythmia risk 3. Genetic studies identify CAMK2D as a druggable target for heart failure prevention 1, and myocardial fibrosis is associated with CAMK2D genetic variation 5. Beyond cardiac function, CAMK2D is expressed during early brain development and heterozygous pathogenic variants cause neurodevelopmental disorders with intellectual disability and delayed speech 4. Emerging evidence suggests CAMK2D involvement in retinal homeostasis through calcium-calmodulin signaling pathways 6. CRISPR-based editing of pathogenic CAMK2D shows therapeutic promise for cardioprotection 7.