Pascal Béguin1,3, Kazuaki Nagashima2, Ramasubbu N. Mahalakshmi1, Réjan Vigot3, Atsuko Matsunaga3, Takafumi Miki4, Mei Yong Ng1, Yu Jin Alvin Ng1, Chiaw Hwee Lim1, Hock Soon Tay5, Le-Ann Hwang5, Dmitri Firsov6, Bor Luen Tang7, Nobuya Inagaki2, Yasuo Mori4, Susumu Seino8, Thomas Launey3*, and Walter Hunziker1,9*
1 Epithelial Cell Biology Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science and Technology (A*STAR), Singapore
2 Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
3 Launey Research Unit for Molecular Neurocybernetics, Riken Brain Science Institute, Wako-shi, Saitama, Japan
4 Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan
5 Monoclonal Antibody Unit, Institute of Molecular and Cell Biology, Agency for Science and Technology (A*STAR), Singapore
6 Pharmacology and Toxicology Department, University of Lausanne, Lausanne, Switzerland
7 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
8 Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
9 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
* Corresponding authors
Published in Journal of Cell Biology on 28 April 2014.
Voltage-gated calcium channels (VGCCs) are key regulators of cell signaling and Ca2+-dependent release of neurotransmitters and hormones. Understanding the mechanisms that inactivate VGCCs to prevent intracellular Ca2+-overload and govern their specific subcellular localization is of critical importance. We report the identification and functional characterization of 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 AID-binding pocket (ABP) 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 Ca2+-channel activity at the plasma membrane, resulting in the inhibition of Ca2+-evoked exocytosis. Thus, BARP can modulate the localization of Cavβ and its assocaition with the Cavα1- subunit to negatively regulate VGCC activity.
Figure legend: Expression of BARP in brain and pancreatic islets. Sections of cortex (a), hippocampus (b) cerebellum (c) and pancreas (d) stained for BARP and analyzed by immunofluorescence microscopy. BARP (red) is detected in cell bodies and the dendritic extensions of pyramidal (green arrow) and Purkinje (white arrows) cells. In pancreatic islets, BARP is expressed in β-cells but absent from α-cells labeled for glucagon (green).
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