Vascular CaMKII: heart and brain in your arteries

Abstract

First characterized in neuronal tissues, the multifunctional calcium/calmodulin-dependent protein kinase II (CaMKII) is a key signaling component in several mammalian biological systems. Its unique capacity to integrate various Ca(2+) signals into different specific outcomes is a precious asset to excitable and nonexcitable cells. Numerous studies have reported roles and mechanisms involving CaMKII in brain and heart tissues. However, corresponding functions in vascular cell types (endothelium and vascular smooth muscle cells) remained largely unexplored until recently. Investigation of the intracellular Ca(2+) dynamics, their impact on vascular cell function, the regulatory processes involved and more recently the spatially restricted oscillatory Ca(2+) signals and microdomains triggered significant interest towards proteins like CaMKII. Heteromultimerization of CaMKII isoforms (four isoforms and several splice variants) expands this kinase's peculiar capacity to decipher Ca(2+) signals and initiate specific signaling processes, and thus controlling cellular functions. The physiological functions that rely on CaMKII are unsurprisingly diverse, ranging from regulating contractile state and cellular proliferation to Ca(2+) homeostasis and cellular permeability. This review will focus on emerging evidence of CaMKII as an essential component of the vascular system, with a focus on the kinase isoform/splice variants and cellular system studied.

Keywords: CaMKII; calcium signaling; endothelium; vascular smooth muscle.

Fig. 1.

Structure and activation of CaMKII. A: each CaMKII monomer consists of a catalytic domain (N-terminal), a regulatory domain and an association domain (C-terminal). The association domain allows CaMKII to form a multimer of 6- to 12 monomers. Autophosphorylation sites (287 and 307) and residues sensitive to oxidation (280 and 281) are conserved among CaMKII isoforms and allow posttranscriptional modulation of the enzyme. B: mechanism of activation of CaMKII. Binding of Ca²⁺/CaM complex to a CaMKII monomer triggers a conformational change, and activates the subunit (Ca²⁺/CaM dependent-activity). The activated (CaM-bound) subunit phosphorylates an adjacent CaM-bound subunit which becomes active in a Ca²⁺/CaM independent-manner. [From Couchonnal and Anderson (30).]

Fig. 2.

CaMKII signaling targets in vascular cells. Schematic summary of CaMKII's targets in endothelial cells (left, blue), smooth muscle cells (right, pink) or shared by both vascular cell types (middle). ROCK, Rho-associated protein kinase; NOS3, nitric oxide synthase 3; JNK, c-Jun NH₂-terminal kinase; Cyt c: cytochrome c; IP₃R, inositol 1,4,5-trisphosphate receptor; CCE, capacitative calcium entry; ERK, extracellular signal-regulated kinase; I_cl, chloride current; NOS2, nitric oxide synthase 2; CREB, cAMP response element-binding protein; MLCK, myosin light chain kinase; LC20, myosin light chain; MEK, mitogen-activated protein kinase kinase; PLA2, phospholipase A2; AA, arachidonic acid; PLB, phospholamban; SERCA, sarco/endoplasmic reticulum Ca²⁺-ATPase; MMP9, matrix metalloproteinase 9; Ca_vβ3, voltage-dependent calcium channel, subunit-β3.