Calcium/Calmodulin-Dependent Protein Kinase II in Cerebrovascular Diseases

Abstract

Cerebrovascular disease is the most common life-threatening and debilitating condition that often leads to stroke. The multifunctional calcium/calmodulin-dependent protein kinase II (CaMKII) is a key Ca²⁺ sensor and an important signaling protein in a variety of biological systems within the brain, heart, and vasculature. In the brain, past stroke-related studies have been mainly focused on the role of CaMKII in ischemic stroke in neurons and established CaMKII as a major mediator of neuronal cell death induced by glutamate excitotoxicity and oxidative stress following ischemic stroke. However, with growing understanding of the importance of neurovascular interactions in cerebrovascular diseases, there are clearly gaps in our understanding of how CaMKII functions in the complex neurovascular biological processes and its contributions to cerebrovascular diseases. Additionally, emerging evidence demonstrates novel regulatory mechanisms of CaMKII and potential roles of the less-studied CaMKII isoforms in the ischemic brain, which has sparked renewed interests in this dynamic kinase family. This review discusses past findings and emerging evidence on CaMKII in several major cerebrovascular dysfunctions including ischemic stroke, hemorrhagic stroke, and vascular dementia, focusing on the unique roles played by CaMKII in the underlying biological processes of neuronal cell death, neuroinflammation, and endothelial barrier dysfunction triggered by stroke. We also highlight exciting new findings, promising therapeutic agents, and future perspectives for CaMKII in cerebrovascular systems.

Keywords: CaMKII; Cerebrovascular disease; Endothelial barrier dysfunction; Neuroinflammation; Neuronal cell death; Stroke; Vascular dementia.

Fig. 1

Diagram of CaMKII structure and mechanisms of activation. a The sequence of CaMKII includes a N-terminal catalytic domain that contains the ATP binding and substrate phosphorylation sites, a regulatory domain that contains the autoinhibitory region, the Ca²⁺/CaM binding site, and multiple post-translational modification sites including phosphorylation sites T253, T286, and T305/306 and the M281/282 oxidation sites, and a C-terminal association domain that mediates multimeric interactions and a variable region that can undergo alternative splicing to generate a variety of CaMKII subtypes. b Schematic depiction of CaMKII holoenzyme with 12 subunits. c Activation mechanism of a CaMKII monomer by the binding of Ca²⁺/CaM and autophosphorylation at T286

Fig. 2

Schematic representation of key roles of CaMKII in the pathogenesis of cerebrovascular diseases. Aberrant activation or expression of CaMKII contributes to the pathophysiology of ischemic stroke by mediating the core signaling events involved in glutamate excitotoxicity, inflammation, oxidative stress, and endothelial barrier dysfunction. CaMKII is also a major regulator of vessel tone and neuronal plasticity in learning and memory and contributes to pathogenesis of subarachnoid hemorrhage (SAH) and vascular dementia