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The HOOK region of voltage-gated Ca2+ channel beta subunits senses and transmits PIP2 signals to the gate

The HOOK region of voltage-gated Ca2+ channel beta subunits senses and transmits PIP2 signals to the gate
Park, Cheon-GyuPark, YongsooSuh, Byung-Chang
DGIST Authors
Park, Cheon-Gyu; Suh, Byung-Chang
Issue Date
Journal of General Physiology, 149(2), 261-276
Article Type
BindingCalcium ChannelDomainFunctional PropertiesIdentificationInactivationPalmitoylationPhosphatasePhosphoinositidesPlasma Membrane
The β subunit of voltage-gated Ca2+ (CaV) channels plays an important role in regulating gating of the a1 pore-forming subunit and its regulation by phosphatidylinositol 4,5-bisphosphate (PIP2). Subcellular localization of the CaV β subunit is critical for this effect; N-terminal-dependent membrane targeting of the β subunit slows inactivation and decreases PIP2 sensitivity. Here, we provide evidence that the HOOK region of the β subunit plays an important role in the regulation of CaV biophysics. Based on amino acid composition, we broadly divide the HOOK region into three domains: S (polyserine), A (polyacidic), and B (polybasic). We show that a β subunit containing only its A domain in the HOOK region increases inactivation kinetics and channel inhibition by PIP2 depletion, whereas a β subunit with only a B domain decreases these responses. When both the A and B domains are deleted, or when the entire HOOK region is deleted, the responses are elevated. Using a peptide-to-liposome binding assay and confocal microscopy, we find that the B domain of the HOOK region directly interacts with anionic phospholipids via polybasic and two hydrophobic Phe residues. The β2c-short subunit, which lacks an A domain and contains fewer basic amino acids and no Phe residues in the B domain, neither associates with phospholipids nor affects channel gating dynamically. Together, our data suggest that the flexible HOOK region of the β subunit acts as an important regulator of CaV channel gating via dynamic electrostatic and hydrophobic interaction with the plasma membrane. © 2017 Park et al.
Rockefeller University Press
Related Researcher
  • Author Suh, Byung-Chang Current Lab
  • 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
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Department of Brain and Cognitive SciencesCurrent Lab1. Journal Articles

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