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Differential effects of RGS proteins on G alpha(q) G alpha(11) activity

机译：RGS蛋白对G alpha（q）G alpha（11）活性的差异作用

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Heterotrimeric G proteins play a pivotal role in GPCR signalling; they link receptors to intracellular effectors and their inactivation by RGS proteins is a key factor in resetting the pathway following stimulation. The precise GPCR:G protein:RGS combination determines the nature and duration of the response. Investigating the activity of particular combinations is difficult in cells which contain multiples of each component. We have therefore utilised a previously characterised yeast system to express mammalian proteins in isolation. Human G alpha(q), and G alpha(11) spontaneously activated the yeast pheromone-response pathway by a mechanism which required the formation of G alpha-GTP. This provided an assay for the specific activity of human RGS proteins. RGS1, RGS2, RGS3 and RGS4 inhibited the spontaneous activity of both G alpha(q), and G alpha(11) but, in contrast, RGS5 and RGS16 were much less effective against G alpha(11) than G alpha(q). Interestingly, RGS2 and RGS3 were able to inhibit signalling from the constitutively active G alpha(QL)(q)/G alpha(QL)(11) mutants, confirming the GAP-independent activity of these RGS proteins. To determine if the RGS-G alpha specificity was maintained under conditions of GPCR stimulation, minor modifications to the C-terminus of G alpha(q)/G alpha(11) enabled coupling to an endogenous receptor. RGS2 and RGS3 were effective inhibitors of both G alpha subunits even at high levels of receptor stimulation, emphasising their GAP-independent activity. At low levels of stimulation RGS5 and RGS 16 retained their differential Got activity, further highlighting that RGS proteins can discriminate between two very closely related Got subunits. (c) 2006 Elsevier Inc. All rights reserved.
机译：异三聚体G蛋白在GPCR信号转导中起关键作用。它们将受体与细胞内效应子相连，RGS蛋白使它们失活是刺激后重置途径的关键因素。精确的GPCR：G蛋白：RGS组合决定了反应的性质和持续时间。在包含多个每种成分的细胞中，调查特定组合的活性非常困难。因此，我们利用了先前表征的酵母系统来分离表达哺乳动物蛋白。人的G alpha（q）和G alpha（11）通过一种需要G alpha-GTP形成的机制自发激活了酵母信息素反应途径。这提供了对人RGS蛋白比活性的测定。 RGS1，RGS2，RGS3和RGS4抑制了G alpha（q）和G alpha（11）的自发活性，但是相比之下，RGS5和RGS16对抗G alpha（11）的效果要比G alpha（q）小得多。有趣的是，RGS2和RGS3能够抑制组成性活性G alpha（QL）（q）/ G alpha（QL）（11）突变体发出的信号，从而证实了这些RGS蛋白的GAP独立活性。为了确定RGS-Gα特异性是否在GPCR刺激条件下得以维持，对G alpha（q）/ G alpha（11）的C末端进行较小的修饰即可偶联至内源性受体。即使在高水平的受体刺激下，RGS2和RGS3也是两个G alpha亚基的有效抑制剂，强调了它们的GAP独立活性。在低水平的刺激下，RGS5和RGS 16保留了它们不同的Got活性，进一步突显了RGS蛋白可以区分两个非常相关的Got亚基。 （c）2006 Elsevier Inc.保留所有权利。

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