Regulation by cAMP-dependent protein kinase of a G-protein-mediated phospholipase C
Regulation by cAMP-dependent protein kinase of a G-protein-mediated phospholipase C
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DOI：
10.1038/382083a0
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发表时间：
1996-07-04
期刊：
影响因子：
64.8
通讯作者：
Simon, MI
中科院分区：
文献类型：
--
作者：
Liu, MY;Simon, MI
异三聚体G蛋白通过将跨膜受体偶联到不同的效应分子，包括腺苷酸环化酶和肌醇-磷脂特异性磷脂酶C (PLC)，介导多种细胞过程（1-3）。腺苷酸环化酶的激活导致环状AMP的产生和camp依赖性蛋白激酶（PKA）的激活，磷脂酶C催化磷脂酰肌醇-4,5-二磷酸（PtdInsP(2)）的水解生成二酰基甘油和肌醇-1,4,5-三磷酸（InsP(3)），导致蛋白激酶C （PKC）的激活和细胞内钙的动员(4)。各种PLC异构体似乎被不同的受体激活，在某些情况下被不同的g蛋白组分激活(5)。plc - β有四种很好的表征形式，它们都在不同程度上被G蛋白的G α (q)家族激活（6-9）。也有报道称g蛋白β γ亚基特异性激活PLC亚型β 2和β 3（10,11）。虽然有人认为PLC的活性可能是由腺苷酸环化酶途径调节的，但这两种途径之间没有明确的联系。在这里，我们报道了camp依赖性蛋白激酶特异性抑制G β γ激活的PLC- β 2活性，但不抑制G α激活的PLC同工酶，并且PKA的作用不会被PKC同工酶模仿。此外，我们发现PKA在体内和体外都能直接磷酸化plc - β 2蛋白的丝氨酸残基。我们的研究结果提供了对两种g蛋白偶联信号转导途径之间串扰的特异性和性质的深入了解。
THE heterotrimeric G proteins mediate a variety of cellular processes by coupling transmembrane receptors to different effector molecules, including adenylyl cyclases and inositol-phospholipid-specific phospholipase C (PLC)(1-3). Activation of adenylyl cyclases results in the production of cyclic AMP and activation of cAMP-dependent protein kinase (PKA), Phospholipase C catalyses the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PtdInsP(2)) to generate diacylglycerol and inositol-1,4,5-triphosphate (InsP(3)), leading to the activation of protein kinase C (PKC) and the mobilization of intracellular calcium(4). The various PLC isoforms appear to be activated by different receptors, and in some cases by different G-protein components(5). There are four well-characterized forms of PLC-beta and all of them are activated to various extents by the G alpha(q) family of G proteins(6-9). Specific activation of PLC isoforms beta 2 and beta 3 by G-protein beta gamma subunits has also been reported(10,11). Although it has been suggested that PLC activity might be modulated by the adenylyl cyclase pathway, no clear link has been established between the two pathways. Here we report that cAMP-dependent protein kinase specifically inhibits G beta gamma-activated PLC-beta 2 activity but not that of the G alpha-activated PLC isoforms, and that the effect of PKA is not mimicked by PKC isozymes. Furthermore, we show that PKA directly phosphorylates serine residues of the PLC-beta 2 protein both in vivo and in vitro. Our results provide an insight into the specificity and nature of the crosstalk between the two G-protein coupled signal transduction pathways.