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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Membrane-localized p-subunits alter the PIP_2 regulation of high-voltage activated Ca~(2+) channels
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Membrane-localized p-subunits alter the PIP_2 regulation of high-voltage activated Ca~(2+) channels

机译：膜定位的p亚基改变高压激活的Ca〜（2+）通道的PIP_2调节。

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摘要

The p-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 p-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 |53-subunit, a cytosolic protein, they can be inhibited by activating a voltage-sensitive lipid phosphatase to deplete PIP_2. When these channels are coex-pressed with a p2a-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-sub-unit. To further test effects of membrane targeting of Ca_v β-sub-units 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 Cav2.2 channels, and increased the current density. In addition, the Lyn-β3 subunit significantly decreased Cav channel inhibition by PIP_2 depletion. Evidently lipidation and membrane anchoring of Cav 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 p2a 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 p-subunit combinations.
机译：电压门控的Ca〜（2+）（Ca_v）通道的p亚基调节高压激活的Ca_v通道的功能表达和几种生物物理特性。我们发现Ca_v p亚基还决定了由膜磷脂磷脂酰肌醇4,5-二磷酸（PIP_2）的通道调节。当Ca_v1.3，-2.1或-2.2通道与| 53-亚基（一种胞质蛋白）共转染时，可以通过激活电压敏感脂质磷酸酶来消耗PIP_2来抑制它们。当这些通道与p2a亚基（棕榈酰化的外周膜蛋白）共表达时，抑制作用要小得多。通过禁用β2a-亚基中的两个棕榈酰化位点可以提高PIP_2的敏感性。为了进一步测试针对Ca_vβ-亚基的膜靶向对PIP_2调控的作用，将Lyn的N末端连接到胞质β3-亚基上以赋予脂质。这种嵌合体，像Ca_vβ2a亚基一样，显示质膜定位，减慢了Cav2.2通道的失活，并增加了电流密度。此外，Lyn-β3亚基显着降低了PIP_2耗尽对Cav通道的抑制作用。显然，Cavβ亚基的脂化和膜锚定与高压激活的Ca_v通道的PIP_2调节竞争。与仅用Ca_vβ3-亚基表达相比，当p2a与β3共表达时，PIP_2耗尽对Ca_v2.2通道的抑制作用会显着减弱。我们的数据表明，神经元中的Ca_v电流会受到膜PIP_2的调节，其程度取决于它们的内源性p-亚基组合。

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    Byung-Chang Suh; Dong-ll Kim; Bjorn H. Falkenburger; Bertil Hille;

  • 作者单位

    Department of Brain Science, Daegu Gyeongbuk Institute of Science and Technology, Daegu 711-873, Korea,Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA 98195-7290;

    Department of Brain Science, Daegu Gyeongbuk Institute of Science and Technology, Daegu 711-873, Korea;

    Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA 98195-7290;

    Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA 98195-7290;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    m1 muscarinic receptor; voltage-sensing phosphatase;

    机译：m1毒蕈碱受体;电压感应磷酸酶;

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