Manning David R
Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, USA.
Sci STKE. 2003 Aug 19;2003(196):pe35. doi: 10.1126/stke.2003.196.pe35.
Examples of the activation of heterotrimeric G proteins in vivo by any means other than through activated cell surface receptors have been limited to pathophysiological phenomena. With the discovery of proteins apart from receptors that facilitate guanine nucleotide exchange and affect G protein subunit dissociation directly, however, the notion of receptor-independent modes of activation in normal circumstances has become a subject of great interest. Three recent publications, each focusing on G protein regulators (GPRs) in asymmetric positioning of the mitotic spindle in the early Caenorhabditis elegans embryo, provide substantial support for the likelihood of such a form of activation. The C. elegans proteins GPR-1 and GPR-2 each contain a G protein regulatory motif, which supports interaction with Galpha(i)-like subunits. Inactivation of the genes encoding GPR-1 and GPR-2 prevents the correct positioning of the mitotic spindle in the one- and two-cell embryo. This phenotype is identical to that achieved by inactivation of genes encoding the Galpha subunits GOA-1 and GPA-16. Because signaling in the one- and two-cell embryos is "intrinsic," the data suggest a GPR-dependent, receptor-independent mode of G protein activation. The GPRs interact preferentially with the guanosine diphosphate (GDP)-bound form of Galpha subunits, and the GPR motif per se exhibits GDP dissociation inhibitor activity. The actions of the GPRs imply that GDP.Galpha.GPR is a key intermediate or effector in force generation relevant to mitotic spindle positioning.
除了通过激活的细胞表面受体外，体内异源三聚体G蛋白以任何其他方式被激活的例子都仅限于病理生理现象。然而，随着除受体之外的能够促进鸟嘌呤核苷酸交换并直接影响G蛋白亚基解离的蛋白质的发现，正常情况下非受体依赖性激活模式的概念已成为一个备受关注的主题。最近的三篇出版物，每一篇都聚焦于秀丽隐杆线虫早期胚胎有丝分裂纺锤体不对称定位中的G蛋白调节剂（GPR），为这种激活形式的可能性提供了大量支持。秀丽隐杆线虫蛋白GPR-1和GPR-2各自包含一个G蛋白调节基序，这支持与Gα(i)样亚基的相互作用。编码GPR-1和GPR-2的基因失活会阻止一细胞和二细胞胚胎中有丝分裂纺锤体的正确定位。这种表型与通过编码Gα亚基GOA-1和GPA-16的基因失活所实现的表型相同。由于一细胞和二细胞胚胎中的信号传导是“内在的”，这些数据表明存在一种GPR依赖性、非受体依赖性的G蛋白激活模式。GPR优先与结合鸟苷二磷酸（GDP）的Gα亚基形式相互作用，并且GPR基序本身具有GDP解离抑制活性。GPR的作用意味着GDP·Gα·GPR是与有丝分裂纺锤体定位相关的力产生中的关键中间体或效应物。
