Ca2+/calmodulin-dependent protein kinase II (CaMKII) exhibits a broad substrate specificity and regulates diverse responses to physiological changes of intracellular Ca2+ concentrations. Five isozymic subunits of the highly abundant brain kinase are encoded by four distinct genes. Expression of each gene is tightly regulated in a cell-specific and developmental manner. CaMKII immunoreactivity is broadly distributed within neurons but is discretely associated with a number of subcellular structures. The unique regulatory properties of CaMKII have attracted a lot of attention. Ca2+/calmodulin-dependent autophosphorylation of a specific threonine residue (alpha-Thr286) within the autoinhibitory domain generates partially Ca(2+)-independent CaMKII activity. Phosphorylation of this threonine in CaMKII is modulated by changes in intracellular Ca2+ concentrations in a variety of cells, and may prolong physiological responses to transient increases in Ca2+. Additional residues within the calmodulin-binding domain are autophosphorylated in the presence of Ca2+ chelators and block activation by Ca2+/calmodulin. This Ca(2+)-independent autophosphorylation is very rapid following prior Ca2+/calmodulin-dependent autophosphorylation at alpha-Thr286 and generates constitutively active, Ca2+/calmodulin-insensitive CaMKII activity. Ca(2+)-independent autophosphorylation of CaMKII also occurs at a slower rate when alpha-Thr286 is not autophosphorylated and results in inactivation of CaMKII. Thus, Ca(2+)-independent autophosphorylation of CaMKII generates a form of the kinase that is refractory to activation by Ca2+/calmodulin. CaMKII phosphorylates a wide range of neuronal proteins in vitro, presumably reflecting its involvement in the regulation of diverse functions such as postsynaptic responses (e.g. long-term potentiation), neurotransmitter synthesis and exocytosis, cytoskeletal interactions and gene transcription. Recent evidence indicates that the levels of CaMKII are altered in pathological states such as Alzheimer's disease and also following ischemia.