Cavβ3 contributes to the maintenance of the blood-brain barrier and alleviates symptoms of experimental autoimmune encephalitis

Brain microvascular endothelial cells (BMECs) are part of the blood-brain barrier (BBB). These cells express Cacnb3 transcripts encoding the Cavβ3 protein, which is a subunit of the voltage-gated Ca2+ (Cav) channels. However, potassium depolarization and electrophysiological recordings in BMECs did not reveal a significant Cav channel function, regardless of the presence or absence of Cavβ3. In vivo, the integrity of the BBB was reduced in the absence of Cavβ3. Following induction of experimental autoimmune encephalomyelitis (EAE), Cavβ3-deficient (Cavβ3-/-) mice showed earlier disease onset with exacerbated clinical disability and increased infiltration of T-cells. In vitro, the trans-endothelial resistance of Cavβ3-/- BMEC monolayers was lower than that of wild-type, permeability to albumin and dextran was increased, and the organization of the junctional protein ZO-1 was impaired in the absence and presence of the pro-inflammatory mediator thrombin. The results suggest that Cavβ3, independent of its function as a subunit of Cav channels, tightly controls cytoplasmic [Ca2+] and Ca2+-dependent MLC phosphorylation and that this role of Cavβ3 in BMECs contributes to the integrity of the BBB and decreases severity of clinical EAE disease.