Direct binding of G-protein beta gamma complex to voltage-dependent calcium channels
Direct binding of G-protein beta gamma complex to voltage-dependent calcium channels
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DOI：
10.1038/385446a0
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发表时间：
1997-01-30
期刊：
影响因子：
64.8
通讯作者：
Campbell, KP
中科院分区：
文献类型：
--
作者：
DeWaard, M;Liu, HY;Campbell, KP
电压依赖性Ca 2+通道在控制突触处的神经递质释放方面发挥核心作用（1，2）。它们可以被某些G蛋白偶联受体抑制，通过膜固有的途径起作用（3-6）。在这里，我们表明，这种抑制作用是由G蛋白β γ复合物和几种类型的这些通道的成孔α（1）亚基之间的直接相互作用引起的（7）。相互作用由连接第一和第二跨膜重复的胞质接头介导。在该接头内，结合发生在α（1）相互作用结构域（AID）（8）和第二下游序列中，所述AID也介导通道的α（1）和β亚基之间的相互作用。结合位点的进一步分析表明，AID中的几个氨基末端残基对G β γ结合至关重要，这定义了一个与羧基末端残基不同的位点，该位点对结合Ca 2+通道的β亚基至关重要（9）。N-末端基序内的精氨酸残基的突变废除β-γ结合，并呈现通道难治性G-蛋白的调制时，在非洲爪蟾卵母细胞中表达，表明的相互作用确实是负责G-蛋白依赖性的Ca 2+通道活性的调制。
Voltage-dependent Ca2+ channels play a central role in controlling neurotransmitter release at the synapse(1,2). They can be inhibited by certain G-protein-coupled receptors, acting by a pathway intrinsic to the membrane(3-6). Here we show that this inhibition results from a direct interaction between the G-protein beta gamma complex and the pore-forming alpha(1) subunits of several types of these channels(7). The interaction is mediated by the cytoplasmic linker connecting the first and second transmembrane repeats. Within this linker, binding occurs both in the alpha(1) interaction domain (AID)(8), which also mediates the interaction between the alpha(1) and beta subunits of tbe channel, and in a second downstream sequence. Further analysis of the binding site showed that several amino-terminal residues in the AID are critical for G beta gamma binding, defining a site distinct from the carboxy-terminal residues shown to be essential for binding the beta-subunit of the Ca2+ channel(9). Mutation of an arginine residue within the N-terminal motif abolished beta gamma binding and rendered the channel refractory to G-protein modulation when expressed in Xenopus oocytes, showing that the interaction is indeed responsible for G-protein-dependent modulation of Ca2+ channel activity.