Heptahelical receptor signaling: beyond the G protein paradigm.
Heptahelical receptor signaling: beyond the G protein paradigm.
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七螺旋受体信号传导：超越 G 蛋白范式。
DOI：
10.1083/jcb.145.5.927
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发表时间：
1999-05-31
期刊：
影响因子：
--
通讯作者：
Lefkowitz RJ
中科院分区：
文献类型：
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作者：
Hall RA;Premont RT;Lefkowitz RJ
七螺旋受体，因其具有七螺旋跨膜跨度的保守结构而被称为七螺旋受体，介导对一系列显著不同的刺激的生理反应。这些包括激素、神经递质、小肽、蛋白质、脂质和离子，以及感官刺激，如气味剂、信息素、苦味和甜味剂以及光子。这个受体超家族包含1,000个成员，使其成为哺乳动物基因组中最大的一类细胞表面分子。此外，最近发现七螺旋受体占秀丽隐杆线虫基因组中总基因的5%（Bargmann，1998），证明了该家族的重要性，并表明这些受体的结构在整个进化过程中高度保守。多年来，该受体家族被称为G蛋白偶联的，该术语基于此类受体与异源三聚体G蛋白相互作用并通过异源三聚体G蛋白发出信号的良好记录范例。简单地说，这种反复验证的范例是，当七螺旋受体被配体刺激时，它们的细胞内区域发生构象变化，使受体与G蛋白相互作用。这种关联反过来又导致G蛋白的构象变化，促进GDP释放和GTP结合，导致G和G亚基的解离。活化的G蛋白亚基然后结合并调节各种细胞内效应物。然而，在过去的几年中，文献中出现了几份报告，描述了七螺旋受体刺激的各种生理后果，令人惊讶的是，似乎不介导的G蛋白活化。同时，用于检测蛋白质-蛋白质相互作用的新技术，如酵母双杂交、噬菌体展示和融合蛋白覆盖，揭示了七螺旋受体与除G蛋白以外的多种细胞内伙伴的关联。这种无法解释的生理学和挑衅性的蛋白质-蛋白质相互作用的融合越来越多地导致人们认识到七螺旋受体信号传导的机制比以前认为的更多样化。这篇简短的评论总结了最近的工作，通过七螺旋受体的细胞内信号转导的方式比经典的G蛋白途径。
HEPTAHELICAL receptors, so called because of their conserved structure featuring seven-helical transmembrane spans, mediate physiological responses to a remarkably diverse array of stimuli. These include hormones, neurotransmitters, small peptides, proteins, lipids and ions, as well as sensory stimuli such as odorants, pheromones, bitter and sweet tastants, and photons. This superfamily of receptors contains 1,000 members, making it the largest class of cell surface molecules in the mammalian genome. Moreover, it was found recently that heptahelical receptors account for 5% of the total genes in the Caenorhabditus elegans genome (Bargmann, 1998), testifying to the importance of this family and demonstrating that the structure of these receptors has been highly conserved throughout evolution. For many years, this family of receptors has been referred to as G protein–coupled, a term based on the well documented paradigm that such receptors interact with and signal through heterotrimeric G proteins. Simply stated, this repeatedly validated paradigm is that when heptahelical receptors are stimulated with ligand, their intracellular regions undergo conformational changes, allowing the receptors to interact with G proteins. This association in turn causes conformational changes in the G proteins that facilitate GDP release and GTP binding, leading to dissociation of G and G subunits. The activated G protein subunits then bind to and regulate various intracellular effectors. During the past few years, however, several reports have appeared in the literature describing various physiological consequences of heptahelical receptor stimulation that, surprisingly, do not seem to be mediated by G protein activation. Concurrently, novel techniques for detecting protein–protein interactions such as yeast two-hybrid, phage display, and fusion protein overlays have revealed associations of heptahelical receptors with a variety of intracellular partners other than G proteins. This convergence of unexplained physiology and provocative protein–protein interactions has led increasingly to the realization that the mechanisms of heptahelical receptor signaling are more diverse than previously thought. This mini-review summarizes recent work on the subject of intracellular signaling by heptahelical receptors through means other than classical G protein pathways.