BARP suppresses voltage-gated calcium channel activity and Ca(2+)-evoked exocytosis

Voltage-gated calcium channels (VGCCs) are key regulators of cell signaling and Ca(2+)-dependent release of neurotransmitters and hormones. Understanding the mechanisms that inactivate VGCCs to prevent intracellular Ca(2+) overload and govern their specific subcellular localization is of critical importance. We report the identification and functional characterization of VGCC β-anchoring and -regulatory protein (BARP), a previously uncharacterized integral membrane glycoprotein expressed in neuroendocrine cells and neurons. BARP interacts via two cytosolic domains (I and II) with all Ca(v)β subunit isoforms, affecting their subcellular localization and suppressing VGCC activity. Domain I interacts at the α(1) interaction domain–binding pocket in Ca(v)β and interferes with the association between Ca(v)β and Ca(v)α1. In the absence of domain I binding, BARP can form a ternary complex with Ca(v)α1 and Ca(v)β via domain II. BARP does not affect cell surface expression of Ca(v)α1 but inhibits Ca(2+) channel activity at the plasma membrane, resulting in the inhibition of Ca(2+)-evoked exocytosis. Thus, BARP can modulate the localization of Ca(v)β and its association with the Ca(v)α1 subunit to negatively regulate VGCC activity.