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首页> 外文期刊>Biochemistry >Fluorescence studies suggest a role for alpha-synuclein in the phosphatidylinositol lipid signaling pathway.
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Fluorescence studies suggest a role for alpha-synuclein in the phosphatidylinositol lipid signaling pathway.

机译：荧光研究表明α-突触核蛋白在磷脂酰肌醇脂质信号通路中的作用。

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Alpha-synuclein plays a key role in the pathogenesis of many neurodegenerative diseases. To date, its cellular role has yet to be determined, although it has been proposed to be connected to calcium and G protein-mediated dopamine signaling. Alpha-synuclein is known to bind strongly to model membrane surfaces where it may interact with other membrane-associated proteins. Here, we find that the membrane association of alpha-synuclein is enhanced by the presence of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)] and Ca(2+). We also find that alpha-synuclein interacts with high affinity with the G protein-regulated enzyme phospholipase Cbeta(2) (PLCbeta(2)), which catalyzes the hydrolysis of PI(4,5)P(2). Binding of alpha-synuclein to PLCbeta(2) reduces its catalytic activity by 50%, but causes its level of activation by Gbetagamma subunits to increase from 4- to 24-fold. This effect is greatly reduced for A53T alpha-synuclein, which is a mutant associated with familial Parkinson's disease. PI(4,5)P(2)hydrolysis by PLCbeta(2) results in an increase in the intracellular Ca(2+) concentration, and we find that in cultured cells the presence of alpha-synuclein results in a 6-fold enhancement in the release of Ca(2+) from intracellular stores in response to agents that release Gbetagamma subunits relative to controls. Alpha-synuclein also enhances the increase in the level of inositol phosphates seen upon G protein stimulation, suggesting that it also may interact with PLCbeta(2) in cells. Given that Ca(2+) and dopamine regulation are mediated through PLCbeta and G protein signals, our results suggest that alpha-synuclein may play a role in inositol phospholipid signaling.
机译：α-突触核蛋白在许多神经退行性疾病的发病机理中起关键作用。迄今为止，尽管已经提出其与钙和G蛋白介导的多巴胺信号传导有关，但其细胞作用尚未确定。已知α-突触核蛋白与模型膜表面牢固结合，在膜表面可能与其他膜相关蛋白相互作用。在这里，我们发现通过磷脂酰肌醇4,5-双磷酸[PI（4,5）P（2）]和Ca（2+）的存在增强了α-突触核蛋白的膜缔合。我们还发现，α-突触核蛋白与G蛋白调节的酶磷脂酶Cbeta（2）（PLCbeta（2）），它催化PI（4,5）P（2）的水解具有高亲和力相互作用。 α-突触核蛋白与PLCbeta（2）的结合将其催化活性降低50％，但导致其被Gbetagamma亚基激活的水平从4倍增加到24倍。对于与家族性帕金森氏病有关的突变体A53Tα-突触核蛋白，该作用大大降低。 PI（4,5）P（2）由PLCbeta（2）水解导致细胞内Ca（2+）浓度增加，并且我们发现在培养的细胞中，α-突触核蛋白的存在导致6倍增强响应于释放相对于对照的Gbetagamma亚基的代理从细胞内存储释放Ca（2+）。 α-突触核蛋白还增强了G蛋白刺激后看到的肌醇磷酸水平的增加，表明它也可能与细胞中的PLCbeta（2）相互作用。鉴于Ca（2+）和多巴胺调节是通过PLCbeta和G蛋白信号介导的，我们的结果表明，α-突触核蛋白可能在肌醇磷脂信号传导中起作用。

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