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Translocatable voltage-gated Ca2+ channel beta subunits in alpha 1-beta complexes reveal competitive replacement yet no spontaneous dissociation

Title
Translocatable voltage-gated Ca2+ channel beta subunits in alpha 1-beta complexes reveal competitive replacement yet no spontaneous dissociation
Authors
Yeon, Jun HeePark, Cheon-GyuHille, BertilSuh, Byung-Chang
DGIST Authors
Yeon, Jun Hee; Park, Cheon-Gyu; Hille, Bertil; Suh, Byung-Chang
Issue Date
2018-10
Citation
Proceedings of the National Academy of Sciences of the United States of America, 115(42), E9934-E9943
Type
Article
Article Type
Article
Author Keywords
voltage-gated Ca2+ channelCa-V beta subunitschemically inducible dimerizationrapamycinPI(4,5)P-2
Keywords
SENSITIVE CALCIUM-CHANNELSKELETAL-MUSCLEINTERACTION DOMAINALPHA(1A) SUBUNITINTERACTION SITEMEMBRANEMODULATIONRECEPTORTRAFFICKINGEXPRESSION
ISSN
0027-8424
Abstract
β subunits of high voltage-gated Ca2+ (CaV) channels promote cellsurface expression of pore-forming α1 subunits and regulate channel gating through binding to the α-interaction domain (AID) in the first intracellular loop. We addressed the stability of CaV α1B-β interactions by rapamycin-translocatable CaV β subunits that allow drug-induced sequestration and uncoupling of the β subunit from CaV2.2 channel complexes in intact cells. Without CaV α1B/α2δ1, all modified β subunits, except membrane-tethered β2a and β2e, are in the cytosol and rapidly translocate upon rapamycin addition to anchors on target organelles: Plasma membrane, mitochondria, or endoplasmic reticulum. In cells coexpressing CaV α1B/α2δ1 subunits, the translocatable β subunits colocalize at the plasma membrane with α1B and stay there after rapamycin application, indicating that interactions between α1B and bound β subunits are very stable. However, the interaction becomes dynamic when other competing β isoforms are coexpressed. Addition of rapamycin, then, switches channel gating and regulation by phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] lipid. Thus, expression of free β isoforms around the channel reveals a dynamic aspect to the α1B-β interaction. On the other hand, translocatable β subunits with AID-binding site mutations are easily dissociated from CaV α1B on the addition of rapamycin, decreasing current amplitude and PI(4,5)P2 sensitivity. Furthermore, the mutations slow CaV2.2 current inactivation and shift the voltage dependence of activation to more positive potentials. Mutated translocatable β subunits work similarly in CaV2.3 channels. In sum, the strong interaction of CaV α1B-β subunits can be overcome by other free β isoforms, permitting dynamic changes in channel properties in intact cells. © 2018 National Academy of Sciences. All Rights Reserved.
URI
http://hdl.handle.net/20.500.11750/9423
DOI
10.1073/pnas.1809762115
Publisher
National Academy of Sciences
Related Researcher
  • Author Suh, Byung-Chang Laboratory of Brain Signal and Synapse Research
  • Research Interests Molecular mechanisms of epilepsy and sensory pain transmission; Signaling mechanism of ion channel regulation and membrane excitability; 분자전기생리; 간질 및 통증의 분자적 기전 연구
Files:
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Collection:
Department of Brain SciencesLaboratory of Brain Signal and Synapse Research1. Journal Articles


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