| CaMKIIδ is the predominant Ca²⁺/calmodulin-dependent protein kinase II isoform in heart that assembles into multimeric holoenzymes and functions as a central integrator of Ca²⁺, β‑adrenergic, and redox signals, translating repetitive Ca²⁺ transients into sustained phosphorylation of ion-handling proteins and transcriptional regulators that drive excitation–contraction coupling, hypertrophic growth, and arrhythmogenesis. The kinase contains an N‑terminal catalytic domain followed by an autoinhibitory region harboring the CaM-binding element and Thr287 autophosphorylation site, and a C‑terminal association domain that promotes oligomerization into dodecamers and larger assemblies; this architecture supports intersubunit autophosphorylation and permits transition from Ca²⁺‑dependent to autonomous activity through Thr287 phosphorylation, methionine oxidation, and O‑GlcNAcylation, so that CaMKIIδ can remain active after the initiating Ca²⁺ pulse. In ventricular myocytes, CaMKIIδ phosphorylates the L‑type Ca²⁺ channel, ryanodine receptor 2, and phospholamban, which increases sarcolemmal Ca²⁺ influx, enhances sarcoplasmic reticulum Ca²⁺ leak, and accelerates SR refilling, and chronic overactivation of this network leads to diastolic Ca²⁺ overload, delayed afterdepolarizations, and triggered activity that underlie ventricular tachycardia and atrial fibrillation. The same kinase also phosphorylates class IIa histone deacetylase HDAC4, leading to its nuclear export and derepression of MEF2‑dependent gene programs, and thereby links Ca²⁺ and neurohumoral stress to hypertrophic gene expression, fibrosis, and adverse remodeling in pressure overload and neurohormone-driven heart disease. Genetic deletion of CaMKIIδ in mice subjected to transverse aortic constriction preserves cardiac hypertrophy but markedly attenuates the transition to heart failure, reducing chamber dilation, systolic dysfunction, fibrosis, apoptosis, and SR Ca²⁺ leak, whereas transgenic overexpression of CaMKIIδ produces action potential prolongation, spontaneous afterdepolarizations, dilated cardiomyopathy, and increased sudden death, confirming this isoform as a critical transducer of pathological cardiac stress. Human failing and ischemic cardiomyopathy samples show elevated CaMKIIδ expression and autonomous activity and increased phosphorylation of downstream Ca²⁺-handling targets, and pharmacologic CaMKII inhibition in structural heart disease models improves left ventricular function and suppresses arrhythmias. |
