Functional implications of CaMKII alternative splicing

Ca2+/calmodulin‐dependent protein kinase II (CaMKII) is known to be a crucial regulator in the post‐synapse during long‐term potentiation. This important protein has been the subject of many studies centered on understanding memory at the molecular, cellular, and organismic level. CaMKII is encoded by four genes in humans, all of which undergo alternative splicing at the RNA level, leading to an enormous diversity of expressed proteins. Advances in sequencing technologies have facilitated the discovery of many new CaMKII transcripts. To date, newly discovered CaMKII transcripts have been incorporated into an ambiguous naming scheme. Herein, we review the initial experiments leading to the discovery of CaMKII and its subsequent variants. We propose the adoption of a new, unambiguous naming scheme for CaMKII variants. Finally, we discuss biological implications for CaMKII splice variants. Alternative splicing produces a diverse range of linkers connecting CaMKII kinase domains to the central holoenzyme hub. We review the exon architecture and splicing rules of CaMKII genes, the 40‐year history of the discovery of CaMKII and its splice variants, and the structural and functional implications of alternative splicing of CaMKII transcripts. Finally, we propose a systematic splice variant naming scheme aimed to resolve decades of confusion in CaMKII variant nomenclature.