Cavβ3 Contributes to the Maintenance of the Blood-Brain Barrier and Alleviates Symptoms of Experimental Autoimmune Encephalomyelitis.

Background: Tight control of cytoplasmic Ca concentration in endothelial cells is essential for the regulation of endothelial barrier function. Here, we investigated the role of Cavβ3, a subunit of voltage-gated Ca (Cav) channels, in modulating Ca signaling in brain microvascular endothelial cells (BMECs) and how this contributes to the integrity of the blood-brain barrier.

Methods: We investigated the function of Cavβ3 in BMECs by Ca imaging and Western blot, examined the endothelial barrier function in vitro and the integrity of the blood-brain barrier in vivo, and evaluated disease course after induction of experimental autoimmune encephalomyelitis in mice using Cavβ3 (Cavβ3-deficient) mice as controls.

Englerin A Inhibits T-Type Voltage-Gated Calcium Channels at Low Micromolar Concentrations.

Englerin A (EA) is a potent agonist of tetrameric transient receptor potential canonical (TRPC) ion channels containing TRPC4 and TRPC5 subunits. TRPC proteins form cation channels that are activated by plasma membrane receptors. They convert extracellular signals such as angiotensin II into cellular responses, whereupon Na and Ca influx and depolarization of the plasma membrane occur.

IP3-dependent Ca signals are tightly controlled by Cavβ3, but not by Cavβ1, 2 and 4.

Independent of its function as a subunit of voltage-gated Ca channels, the Cavβ3 subunit desensitizes fibroblasts and pancreatic β-cells to low concentrations of inositol-1,4,5-trisphosphate (IP3). This alters agonist-induced Ca signaling and cellular functions, for example, insulin secretion and wound healing. A total of four Cavβ subunits exist, Cavβ1, Cavβ2, Cavβ3, and Cavβ4.

Cavβ3 Regulates Ca Signaling and Insulin Expression in Pancreatic β-Cells in a Cell-Autonomous Manner.

Voltage-gated Ca (Cav) channels consist of a pore-forming Cavα1 subunit and auxiliary Cavα2-δ and Cavβ subunits. In fibroblasts, Cavβ3, independent of its role as a Cav subunit, reduces the sensitivity to low concentrations of inositol-1,4,5-trisphosphate (IP). Similarly, Cavβ3 could affect cytosolic calcium concentration ([Ca ]) in pancreatic β-cells.

IP Receptor-Dependent Cytoplasmic Ca Signals Are Tightly Controlled by Cavβ3.

Voltage-gated calcium channels (Cavs) are major Ca entry pathways in excitable cells. Their β subunits facilitate membrane trafficking of the channel's ion-conducting α1 pore and modulate its gating properties. We report that one β subunit, β3, reduces Ca release following stimulation of phospholipase C-coupled receptors and inositol 1,4,5-trisphosphate (IP) formation.