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Membrane-localized beta-subunits alter the PIP2 regulation of high-voltage activated Ca2+ channels
- Membrane-localized beta-subunits alter the PIP2 regulation of high-voltage activated Ca2+ channels
- Suh, BC[Suh, Byung-Chang]; Kim, DI[Kim, Dong-Il]; Falkenburger, BH[Falkenburger, Bjoern H.]; Hille, B[Hille, Bertil]
- DGIST Authors
- Suh, BC[Suh, Byung-Chang]; Kim, DI[Kim, Dong-Il]
- Issue Date
- Proceedings of the National Academy of Sciences of the United States of America, 109(8), 3161-3166
- Article Type
- Amino Terminal Sequence; Animals; Calcium Channels; Calcium Current; Cell Membrane; Chimeric Protein; Controlled Study; Enzyme Activation; Genetic Transfection; HEK293 Cells; Humans; Ion Channel Gating; Lipoylation; M1 Muscarinic Receptor; Nerve Cell; Palmitoylation; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol 4,5 Bisphosphate; Phosphoprotein Phosphatases; Priority Journal; Protein Kinase Lyn; Protein Subunit; Protein Subunits; Protein Transport; Regulatory Mechanism; Unclassified Drug; Voltage-Gated Calcium Channel; Voltage-Gated Calcium Channel 1.3; Voltage-Gated Calcium Channel 2.1; Voltage-Gated Calcium Channel 2.2; Voltage-Gated Calcium Channel Beta2A Subunit; Voltage-Gated Calcium Channel Beta3 Subunit; Voltage-Sensing Phosphatase; Zebrafish
- The β-subunits of voltage-gated Ca 2+ (Ca V) channels regulate the functional expression and several biophysical properties of high-voltage-activated Ca V channels. We find that Ca V β-subunits also determine channel regulation by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP 2). When Ca V1.3, -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 PIP 2. When these channels are coexpressed with a β2a-subunit, a palmitoylated peripheral membrane protein, the inhibition is much smaller. PIP 2 sensitivity could be increased by disabling the two palmitoylation sites in the β2a-subunit. To further test effects of membrane targeting of Ca V β-subunits on PIP 2 regulation, the N terminus of Lyn was ligated onto the cytosolic β3-subunit to confer lipidation. This chimera, like the Ca V β2a-subunit, displayed plasma membrane localization, slowed the inactivation of Ca V2.2 channels, and increased the current density. In addition, the Lyn-β3 subunit significantly decreased Ca Vchannel inhibition by PIP 2 depletion. Evidently lipidation and membrane anchoring of Ca V β-subunits compete with the PIP 2 regulation of high-voltage-activated Ca V channels. Compared with expression with Ca V β3-subunits alone, inhibition of Ca V2.2 channels by PIP 2 depletion could be significantly attenuated when β2a was coexpressed with β3. Our data suggest that the Ca V currents in neurons would be regulated by membrane PIP 2 to a degree that depends on their endogenous β-subunit combinations.
- National Academy of Sciences
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