Plasma membrane targeting is essential for Rem-mediated Ca2+ channel inhibition
Plasma membrane targeting is essential for Rem-mediated Ca2+ channel inhibition
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DOI：
10.1074/jbc.m706176200
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发表时间：
2007-09-28
影响因子：
4.8
通讯作者：
Andres, Douglas A.
中科院分区：
文献类型：
--
作者：
Correll, Robert N.;Pang, Chunyan;Andres, Douglas A.
小 GTPase Rem 是高压激活 Ca2+ 通道的有效负调节剂，也是 Ca2+ 通道辅助 β 亚基的已知相互作用伙伴。 Rem 介导的通道抑制机制仍存在争议，尽管有人提出 Ca-V β 关联是必需的。先前的研究表明，Rem (Rem-(1-265)) C 端截短显示体内与膜定位 β 2a 的结合减少，并且缺乏通道调节功能。在本文中，我们描述了 Rem C 末端通过与磷脂酰肌醇脂质结合在质膜定位中的作用。此外，Rem-(1-265) 可以在体外与 β 2a 结合，在体内与 β 1b 结合，表明 C 末端不直接参与 Ca-V β 结合。尽管已证明具有 β 1b 结合作用，但 Rem-(1-265) 无法调节 CaV1.2-β 1b 通道复合物，表明 β 亚基结合不足以调节通道。然而，K-Ras4B 或 H-Ras 的 CAAX 结构域与 Rem-(1-265) C 末端的融合恢复了膜定位和 Ca2+ 通道调节，表明 β 结合和膜定位是通道抑制所需的独立事件。
The small GTPase Rem is a potent negative regulator of high voltage-activated Ca2+ channels and a known interacting partner for Ca2+ channel accessory beta subunits. The mechanism for Rem-mediated channel inhibition remains controversial, although it has been proposed that Ca-V beta association is required. Previous work has shown that a C-terminal truncation of Rem (Rem-(1-265)) displays reduced in vivo binding to membrane-localized beta 2a and lacks channel regulatory function. In this paper, we describe a role for the Rem C terminus in plasma membrane localization through association with phosphatidylinositol lipids. Moreover, Rem-(1-265) can associate with beta 2a in vitro and beta 1b in vivo, suggesting that the C terminus does not directly participate in Ca-V beta association. Despite demonstrated beta 1b binding, Rem-(1-265) was not capable of regulating a CaV1.2-beta 1b channel complex, indicating that beta subunit binding is not sufficient for channel regulation. However, fusion of the CAAX domain from K-Ras4B or H-Ras to the Rem-(1-265) C terminus restored membrane localization and Ca2+ channel regulation, suggesting that beta binding and membrane localization are independent events required for channel inhibition.