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BARP suppresses voltage-gated calcium channel activity and Ca2+-evoked exocytosis.

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 ?-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 Cav? subunit isoforms, affecting their subcellular localization and suppressing VGCC activity. Domain I interacts at the ?1 interaction domain-binding pocket in Cav? and interferes with the association between Cav? and Cav?1. In the absence of domain I binding, BARP can form a ternary complex with Cav?1 and Cav? via domain II. BARP does not affect cell surface expression of Cav?1 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 Cav? and its association with the Cav?1 subunit to negatively regulate VGCC activity.

SUBMITTER: Beguin P

PROVIDER: S-EPMC4003244 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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BARP suppresses voltage-gated calcium channel activity and Ca2+-evoked exocytosis.

Béguin Pascal P Nagashima Kazuaki K Mahalakshmi Ramasubbu N RN Vigot Réjan R Matsunaga Atsuko A Miki Takafumi T Ng Mei Yong MY Ng Yu Jin Alvin YJ Lim Chiaw Hwee CH Tay Hock Soon HS Hwang Le-Ann LA Firsov Dmitri D Tang Bor Luen BL Inagaki Nobuya N Mori Yasuo Y Seino Susumu S Launey Thomas T Hunziker Walter W

The Journal of cell biology 20140421 2

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 neur ...[more]

PMID: 24751537

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Project description:Study objectivesVoltage-gated Ca(2+) channels (VGCCs) are key elements in mediating thalamocortical rhythmicity. Low-voltage activated (LVA) CaV 3 T-type Ca(2+) channels have been related to thalamic rebound burst firing and to generation of non-rapid eye movement (NREM) sleep. High-voltage activated (HVA) CaV 1 L-type Ca(2+) channels, on the opposite, favor the tonic mode of action associated with higher levels of vigilance. However, the role of the HVA Non-L-type CaV2.3 Ca(2+) channels, which are predominantly expressed in the reticular thalamic nucleus (RTN), still remains unclear. Recently, CaV2.3(-/-) mice were reported to exhibit altered spike-wave discharge (SWD)/absence seizure susceptibility supported by the observation that CaV2.3 mediated Ca(2+) influx into RTN neurons can trigger small-conductance Ca(2+)-activated K(+)-channel type 2 (SK2) currents capable of maintaining thalamic burst activity. Based on these studies we investigated the role of CaV2.3 R-type Ca(2+) channels in rodent sleep.MethodsThe role of CaV2.3 Ca(2+) channels was analyzed in CaV2.3(-/-) mice and controls in both spontaneous and artificial urethane-induced sleep, using implantable video-EEG radiotelemetry. Data were analyzed for alterations in sleep architecture using sleep staging software and time-frequency analysis.ResultsCaV2.3 deficient mice exhibited reduced wake duration and increased slow-wave sleep (SWS). Whereas mean sleep stage durations remained unchanged, the total number of SWS epochs was increased in CaV2.3(-/-) mice. Additional changes were observed for sleep stage transitions and EEG amplitudes. Furthermore, urethane-induced SWS mimicked spontaneous sleep results obtained from CaV2.3 deficient mice. Quantitative Real-time PCR did not reveal changes in thalamic CaV3 T-type Ca(2+) channel expression. The detailed mechanisms of SWS increase in CaV2.3(-/-) mice remain to be determined.ConclusionsLow-voltage activated CaV2.3 R-type Ca(2+) channels in the thalamocortical loop and extra-thalamocortical circuitries substantially regulate rodent sleep architecture thus representing a novel potential target for pharmacological treatment of sleep disorders in the future.

Dataset Information

BARP suppresses voltage-gated calcium channel activity and Ca2+-evoked exocytosis.

Publications

BARP suppresses voltage-gated calcium channel activity and Ca2+-evoked exocytosis.

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