Endothelial calcium dynamics, connexin channels and blood-brain barrier function

Abstract

Situated between the circulation and the brain, the blood-brain barrier (BBB) protects the brain from circulating toxins while securing a specialized environment for neuro-glial signaling. BBB capillary endothelial cells exhibit low transcytotic activity and a tight, junctional network that, aided by the cytoskeleton, restricts paracellular permeability. The latter is subject of extensive research as it relates to neuropathology, edema and inflammation. A key determinant in regulating paracellular permeability is the endothelial cytoplasmic Ca(2+) concentration ([Ca(2+)]i) that affects junctional and cytoskeletal proteins. Ca(2+) signals are not one-time events restricted to a single cell but often appear as oscillatory [Ca(2+)]i changes that may propagate between cells as intercellular Ca(2+) waves. The effect of Ca(2+) oscillations/waves on BBB function is largely unknown and we here review current evidence on how [Ca(2+)]i dynamics influence BBB permeability.

Keywords: ARC; BBB; BCEC; BK; Blood–brain barrier; CRAC; Ca(2+) dynamics; Ca(2+) release-activated channels; Ca(2+)/calmodulin-dependent kinase II; CaM; CaMKII; Connexin channels; Cx; ER; Endothelial permeability; G-protein coupled receptor; GPCR; ICAM1; InsP(3); InsP(3)R; MAPK; MDCK; MLC; MLCK; MMP; Madine–Darby canine kidney cells; N-methyl-d-aspartate-sensitive receptor; NADPH oxidase; NFκB; NMDA-R; NOS; PAR; PKC; PLA2; PLC; ROS; STIM; TRP; VASP; VEGF; ZO; arachidonate-regulated Ca(2+) entry channels; blood–brain barrier; bovine brain capillary endothelial cells; bradykinin; cGMP; calmodulin; connexin; cyclic guanosine monophosphate; endoplasmic reticulum; inositol 1,4,5-trisphosphate; inositol 1,4,5-trisphosphate receptor; intercellular adhesion molecule 1; matrix-metalloproteinase; mitogen-activated protein kinase; myosin light chain; myosin light chain kinase; nicotinamide adenine dinucleotide phosphate oxidase; nitric oxide synthase; nuclear factor κB; p/sGC; particulate/soluble guanylyl cyclase; phospholipase A2; phospholipase C; protease-activated receptor; protein kinase C; reactive oxygen species; stromal interaction molecule; transient receptor potential; vascular endothelial growth factor; vasodilator-stimulated phosphoprotein; zonula occludens.