Switching of the coupling of the beta(2)-adrenergic receptor to different G proteins by protein kinase A
Switching of the coupling of the beta(2)-adrenergic receptor to different G proteins by protein kinase A
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DOI：
10.1038/36362
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发表时间：
1997-11-06
期刊：
影响因子：
64.8
通讯作者：
Lefkowitz, RJ
中科院分区：
文献类型：
--
作者：
Daaka, Y;Luttrell, LM;Lefkowitz, RJ
许多与细胞表面结合的G-Grotein偶联激素受体可以通过几种不同类别的G蛋白(1-4)向细胞内部发出信号。例如，尽管原型β(2)-肾上腺素能受体的大部分作用是通过G(S)蛋白和环腺苷依赖的蛋白激酶系统(5，6)介导的，但β-肾上腺素能受体也可以与G(I)蛋白(1，2)偶联。在这里，我们研究控制这种耦合的专一性的机制。我们发现，在HEK293细胞中，β(2)-肾上腺素能受体对丝裂原活化蛋白(MAP)激酶的刺激是由百日咳毒素敏感G蛋白的β-γ亚基通过涉及非受体酪氨酸激酶c-Src和G蛋白RAS的途径来介导的，该途径被β(2)-肾上腺素能受体激活需要该受体被PKA磷酸化，因为它被PKA的抑制剂H-89所阻断。此外，该受体的一个突变体，它缺乏正常情况下被PKA磷酸化的位点，可以激活腺苷环化酶(5)，该酶产生cAMP，但不能激活MAP激酶。我们的结果表明，先前已证明的一种机制，即介导β(2)-肾上腺素能受体从G(S)去偶联从而异源脱敏(PKA介导的受体磷酸化)，也有助于将该受体从G(S)‘切换’到G(I)，并启动一系列新的信号事件。
Many of the G-grotein-coupled receptors for hormones that bind to the cell surface can signal to the interior of the cell through several different classes of G protein(1-4). Far example, although most of the actions of the prototype beta(2)-adrenergic receptor are mediated through G(s) proteins and thr cyclic-AMP-dependent protein kinase (PKA) system(5,6), beta-adrenergis receptors can also couple to G(i) proteins(1,2). Here we investigate the mechanism that controls the specificity of this coupling. We show that in HEK293 cells, stimulation of mitogen-activated protein (MAP) kinase by the beta(2)-adrenergic receptor is mediated by the beta gamma subunits of pertussis-toxin-sensitive G proteins through a pathway involving the non-receptor tyrosine kinase c-Src and the G protein Ras, Activation of this pathway by the beta(2)-adrenergic receptor requires that the receptor be phosphorylated by PKA because it is blocked by H-89, an inhibitor of PKA. Additionally, a mutant of the receptor, which lacks the sites normally phosphorylated by PKA, can activate adenylyl cyclase(5), the enzyme that generates cAMP, but not MAP kinase. Our results demonstrate that a mechanism previously shown to mediate uncoupling of the beta(2)-adrenergic receptor from G(s) and thus heterologous desensitization(7) (PKA-mediated receptor phosphorylation), also serves to 'switch' coupling of this receptor from G(s) to G(i) and initiate a new set of signalling events.