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Published on: May 25, 2011
BARP suppresses voltage-gated calcium channel activity and Ca2+-evoked exocytosis
Pascal Béguin1, Kazuaki Nagashima, Ramasubbu N Mahalakshmi
1Epithelial Cell Biology Laboratory and 2 Monoclonal Antibody Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673.
Abstract:
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 Cavβ subunit isoforms, affecting their subcellular localization and suppressing VGCC activity. Domain I interacts at the α1 interaction domain-binding pocket in Cavβ and interferes with the association between Cavβ and Cavα1. In the absence of domain I binding, BARP can form a ternary complex with Cavα1 and Cavβ via domain II. BARP does not affect cell surface expression of Cavα1 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 Cavβ and its association with the Cavα1 subunit to negatively regulate VGCC activity.
Insights
Voltage-gated calcium channels (VGCCs) are regulated by a new protein, VGCC β-anchoring and -regulatory protein (BARP). BARP suppresses VGCC activity by altering Cavβ subunit localization and interaction with Cavα1, inhibiting calcium influx and exocytosis.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Voltage-gated calcium channels (VGCCs) are crucial for cell signaling, neurotransmitter release, and hormone secretion.
- Mechanisms controlling VGCC inactivation and subcellular localization are vital for preventing calcium overload.
- Neuroendocrine cells and neurons rely on precise regulation of calcium influx.
Purpose of the Study:
- To identify and characterize novel proteins regulating VGCCs.
- To elucidate the function of VGCC β-anchoring and -regulatory protein (BARP) in neuroendocrine cells and neurons.
- To understand how BARP modulates VGCC activity and localization.
Main Methods:
- Identification and functional characterization of BARP.
- Analysis of BARP interactions with VGCC subunits (Cavα1 and Cavβ).
- Investigation of BARP's effect on VGCC activity and Ca(2+)-evoked exocytosis.
Main Results:
- BARP, an integral membrane glycoprotein, interacts with all Cavβ subunit isoforms via two cytosolic domains.
- BARP binding interferes with Cavβ and Cavα1 association, modulating VGCC localization and activity.
- BARP inhibits plasma membrane VGCC activity and Ca(2+)-evoked exocytosis without affecting Cavα1 cell surface expression.
Conclusions:
- BARP negatively regulates VGCC activity by modulating Cavβ subunit localization and its association with Cavα1.
- BARP plays a significant role in controlling calcium signaling and exocytosis in neuroendocrine cells and neurons.
- BARP represents a novel target for understanding and potentially manipulating VGCC function.
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