Loss of signaling through the G protein, Gz, results in abnormal platelet activation and altered responses to psychoactive drugs.
Loss of signaling through the G protein, Gz, results in abnormal platelet activation and altered responses to psychoactive drugs.
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DOI：
10.1073/pnas.180194597
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发表时间：
2000-08
影响因子：
11.1
通讯作者：
Jing Yang;Jie Wu;M. Kowalska;A. Dalvi;N. Prévost;P. O'Brien;D. Manning;M. Poncz;I. Lucki;J. Blendy;L. Brass
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文献类型：
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作者：
Jing Yang;Jie Wu;M. Kowalska;A. Dalvi;N. Prévost;P. O'Brien;D. Manning;M. Poncz;I. Lucki;J. Blendy;L. Brass
异三聚体G蛋白通过连接细胞表面受体和细胞内信号通路介导细胞对外部事件反应的最早步骤。G(z)是G蛋白G(i)家族的成员，在血小板和脑中显著表达。在这里，我们发现小鼠G(z) α亚基的缺失：(i)通过阻止正常肾上腺素生理浓度下cAMP形成的抑制而损害血小板聚集，（ii）导致小鼠对致命的血栓栓塞更有抵抗力。G（zalpha）的缺失也会导致对可卡因的过度反应，降低吗啡的镇痛作用，并消除作为儿茶酚胺再摄取抑制剂的广泛使用的抗抑郁药物的作用。尽管在相同的细胞中存在其他G（α）家族成员，但这些变化仍会发生，并且不伴有其他G蛋白亚基表达水平的可检测的代偿性变化。因此，这些结果为G蛋白之间的受体选择性提供了见解，并为理解血小板功能和精神活性药物的作用提供了模型。
Heterotrimeric G proteins mediate the earliest step in cell responses to external events by linking cell surface receptors to intracellular signaling pathways. G(z) is a member of the G(i) family of G proteins that is prominently expressed in platelets and brain. Here, we show that deletion of the alpha subunit of G(z) in mice: (i) impairs platelet aggregation by preventing the inhibition of cAMP formation normally seen at physiologic concentrations of epinephrine, and (ii) causes the mice to be more resistant to fatal thromboembolism. Loss of G(zalpha) also results in greatly exaggerated responses to cocaine, reduces the analgesic effects of morphine, and abolishes the effects of widely used antidepressant drugs that act as catecholamine reuptake inhibitors. These changes occur despite the presence of other G(ialpha) family members in the same cells and are not accompanied by detectable compensatory changes in the level of expression of other G protein subunits. Therefore, these results provide insights into receptor selectivity among G proteins and a model for understanding platelet function and the effects of psychoactive drugs.