HORMONAL-STIMULATION OF ADENYLYL CYCLASE THROUGH GI-PROTEIN BETA-GAMMA-SUBUNITS
HORMONAL-STIMULATION OF ADENYLYL CYCLASE THROUGH GI-PROTEIN BETA-GAMMA-SUBUNITS
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DOI：
10.1038/356159a0
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发表时间：
1992-03-12
期刊：
影响因子：
64.8
通讯作者：
BOURNE, HR
中科院分区：
文献类型：
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作者：
FEDERMAN, AD;CONKLIN, BR;BOURNE, HR
激动剂结合受体通过催化与α亚基结合的GDP被GTP取代来激活异三聚体（α-β-γ）G蛋白，导致α-GTP从β-γ亚基上解离。在大多数情况下，α-GTP将信号传递给效应物，如分别通过α（s）和α（i）对腺苷酸环化酶的激素刺激1-4和抑制5，6。相比之下，酵母7中的遗传证据和哺乳动物细胞8-10中的研究表明，G蛋白的β-γ-亚基也可能调节效应子途径。实际上，在可用于研究11-14的四种重组哺乳动物腺苷酸环化酶中，两种腺苷酸环化酶II和IV被β-γ刺激。β-γ的这种作用需要α（s）-GTP的共刺激14，15。这种效应器反应性的条件模式导致了预测15，即与许多G蛋白偶联的受体将介导细胞环AMP的升高，前提是G（s）也是活性的。我们现在证实了这一预测。突变活性α与腺苷酸环化酶II的共表达将通过“抑制性”受体（与G（i）偶联）起作用的激动剂转化为cAMP合成的刺激剂。使用百日咳毒素和β-γ（transducin的α-亚基）的假定清除剂进行的实验表明，G（i）蛋白的β-γ-亚基介导了这种刺激。这些发现为G（i）蛋白的β-γ-亚基分配了一种新的信号功能，即腺苷酸环化酶II对cAMP合成的条件刺激。
AGONIST-BOUND receptors activate heterotrimeric (alpha-beta-gamma) G proteins by catalysing replacement by GTP of GDP bound to the alpha-subunit, resulting in dissociation of alpha-GTP from the beta-gamma-subunits. In most cases, alpha-GTP carries the signal to effectors, as in hormonal stimulation 1-4 and inhibition 5,6 of adenylyl cyclase by alpha(s) and alpha(i) respectively. By contrast, genetic evidence in yeast 7 and studies in mammalian cells 8-10 suggest that beta-gamma-subunits of G proteins may also regulate effector pathways. Indeed, of the four recombinant mammalian adenylyl cyclases available for study 11-14, two, adenylyl cyclases II and IV, are stimulated by beta-gamma. This effect of beta-gamma requires costimulation by alpha(s)-GTP 14,15. This conditional pattern of effector responsiveness led to the prediction 15 that receptors coupled to many G proteins will mediate elevation of cellular cyclic AMP, provided that G(s) is also active. We now confirm this prediction. Coexpression of mutationally active alpha(s) with adenylyl cyclase II converted agonists that act through 'inhibitory' receptors (coupled to G(i)) into stimulators of cAMP synthesis. Experiments using pertussis toxin and a putative scavenger of beta-gamma, the alpha-subunit of transducin, suggest that beta-gamma-subunits of the G(i) proteins mediated this stimulation. These findings assign a new signalling function to beta-gamma-subunits of G(i) proteins, the conditional stimulation of cAMP synthesis by adenylyl cyclase II.