G-protein-coupled Receptor Kinase-interacting Proteins Inhibit Apoptosis by Inositol 1,4,5-Triphosphate Receptor-mediated Ca2+ Signal Regulation*
G-protein-coupled Receptor Kinase-interacting Proteins Inhibit Apoptosis by Inositol 1,4,5-Triphosphate Receptor-mediated Ca2+ Signal Regulation*
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DOI：
10.1074/jbc.m109.041509
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发表时间：
2009-08
期刊：
影响因子：
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通讯作者：
Songbai Zhang;C. Hisatsune;T. Matsu-ura;K. Mikoshiba
中科院分区：
文献类型：
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作者：
Songbai Zhang;C. Hisatsune;T. Matsu-ura;K. Mikoshiba
三磷酸肌醇（inositol 1，4，5-trisphosphate，IP 3）受体（inositol 1，4，5-trisphosphate receptor，IP 3R）是一种细胞内IP 3门控的钙离子通道，在多种钙离子依赖的细胞反应中起着重要的调节作用。许多细胞内调节剂和IP 3R结合蛋白调节IP 3R通道功能。在这里，我们确定了G蛋白偶联受体激酶相互作用蛋白（GIT），GIT 1和GIT 2，作为新的IP 3R结合蛋白。我们发现GIT 1和GIT 2都直接与IP 3R的所有三种亚型结合。这种相互作用受到胞浆Ca 2+浓度的影响，并在功能上抑制IP 3R活性。敲低GIT诱导和加速半胱天冬酶依赖性细胞凋亡在未受刺激和星形孢菌素处理的细胞，这是减弱野生型GIT 1过表达或IP 3R的药理学抑制剂，但不是由GIT 1的突变形式，废除的相互作用。因此，我们得出结论，GIT通过调节IP 3R介导的Ca 2+信号，通过直接与IP 3R在胞浆Ca 2+依赖的方式相互作用，抑制细胞凋亡。
The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is an intracellular IP3-gated calcium (Ca2+) release channel and plays important roles in regulation of numerous Ca2+-dependent cellular responses. Many intracellular modulators and IP3R-binding proteins regulate the IP3R channel function. Here we identified G-protein-coupled receptor kinase-interacting proteins (GIT), GIT1 and GIT2, as novel IP3R-binding proteins. We found that both GIT1 and GIT2 directly bind to all three subtypes of IP3R. The interaction was favored by the cytosolic Ca2+ concentration and it functionally inhibited IP3R activity. Knockdown of GIT induced and accelerated caspase-dependent apoptosis in both unstimulated and staurosporine-treated cells, which was attenuated by wild-type GIT1 overexpression or pharmacological inhibitors of IP3R, but not by a mutant form of GIT1 that abrogates the interaction. Thus, we conclude that GIT inhibits apoptosis by modulating the IP3R-mediated Ca2+ signal through a direct interaction with IP3R in a cytosolic Ca2+-dependent manner.