NDLI: Membrane-localized β-subunits alter the PIP2 regulation of high-voltage activated Ca2+ channels

Content Provider	PubMed Central
Author	Suh, Byung-chang Kim, Dong-il Falkenburger, Björn H. Hille, Bertil
Abstract	The β-subunits of voltage-gated Ca2+ (CaV) channels regulate the functional expression and several biophysical properties of high-voltage–activated CaV channels. We find that CaV β-subunits also determine channel regulation by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2). When CaV1.3, -2.1, or -2.2 channels are cotransfected with the β3-subunit, a cytosolic protein, they can be inhibited by activating a voltage-sensitive lipid phosphatase to deplete PIP2. When these channels are coexpressed with a β2a-subunit, a palmitoylated peripheral membrane protein, the inhibition is much smaller. PIP2 sensitivity could be increased by disabling the two palmitoylation sites in the β2a-subunit. To further test effects of membrane targeting of CaV β-subunits on PIP2 regulation, the N terminus of Lyn was ligated onto the cytosolic β3-subunit to confer lipidation. This chimera, like the CaV β2a-subunit, displayed plasma membrane localization, slowed the inactivation of CaV2.2 channels, and increased the current density. In addition, the Lyn-β3 subunit significantly decreased CaV channel inhibition by PIP2 depletion. Evidently lipidation and membrane anchoring of CaV β-subunits compete with the PIP2 regulation of high-voltage–activated CaV channels. Compared with expression with CaV β3-subunits alone, inhibition of CaV2.2 channels by PIP2 depletion could be significantly attenuated when β2a was coexpressed with β3. Our data suggest that the CaV currents in neurons would be regulated by membrane PIP2 to a degree that depends on their endogenous β-subunit combinations.
Related Links	http://dx.doi.org/10.1073/pnas.1121434109
Starting Page	3161
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	8
Volume Number	109
Language	English
Publisher	National Academy of Sciences
Publisher Date	2012-02-21
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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