Nuclear CaMKII Isoforms as Regulators of Transcription: From Developmental to Pathological Persistence.

Calcium/calmodulin-dependent protein kinase II (CaMKII) comprises multiple isoforms with distinct nuclear variants that exert transcriptional control in a context-dependent manner. Among them, CaMKIIδB and δ9 in the heart, and CaMKIIγ in the nervous system, have emerged as regulators of chromatin dynamics, transcription factor activity, and developmental gene programs. Nuclear localization is driven by splice-dependent nuclear localization sequences, with phosphorylation at defined serine residues modulating import and retention. Evidence supports CaMKII-dependent phosphorylation of class IIa HDACs (Ser467/Ser632 in HDAC4), linking CaMKII to MEF2 activation in cardiac hypertrophy, and interactions with NF-κB and HSF1 further expand its nuclear repertoire. In the nervous system, CaMKIIγ contributes to kinase-dependent gene expression, potentially influencing plasticity and disease susceptibility. While these mechanisms highlight nuclear CaMKII as an isoform-specific regulator of transcription, direct evidence remains elusive, and several CaMKII putative substrates require further validation. This review synthesizes current knowledge on nuclear CaMKII isoforms, emphasizes established mechanistic pathways, and outlines unsolved questions critical for understanding their roles in development, disease progression, and therapeutic targeting.