Siekhaus Daria E, Drubin David G
Department of Molecular and Cell Biology, University of California Berkeley, 401 Barker Hall, Berkeley, CA 94720-3202, USA.
Nat Cell Biol. 2003 Mar;5(3):231-5. doi: 10.1038/ncb941.
Tripartite G-protein-coupled receptors (GPCRs) represent one of the largest groups of signal transducers, transmitting signals from hormones, neuropeptides, odorants, food and light. Ligand-bound receptors catalyse GDP/GTP exchange on the G-protein alpha-subunit (Galpha), leading to alpha-GTP separation from the betagamma subunits and pathway activation. Activating mutations in the receptors or G proteins underlie many human diseases, including some cancers, dwarfism and premature puberty. Regulators of G-protein signalling (RGS proteins) are known to modulate the level and duration of ligand-induced signalling by accelerating the intrinsic GTPase activity of the Galpha subunit, and thus reformation of the inactive GDP-bound Galpha. Here we find that even in the absence of receptor, mutation of the RGS family member Sst2 (refs 6-9) permits spontaneous activation of the G-protein-coupled mating pathway in Saccharomyces cerevisiae at levels normally seen only in the presence of ligand. Our work demonstrates the occurrence of spontaneous tripartite G-protein signalling in vivo and identifies a requirement for RGS proteins in preventing such receptor-independent activation.
三聚体G蛋白偶联受体(GPCRs)是最大的信号转导器群体之一,可传递来自激素、神经肽、气味分子、食物和光线的信号。配体结合的受体催化G蛋白α亚基(Gα)上的GDP/GTP交换,导致α-GTP与βγ亚基分离并激活信号通路。受体或G蛋白中的激活突变是许多人类疾病的基础,包括某些癌症、侏儒症和性早熟。已知G蛋白信号调节剂(RGS蛋白)通过加速Gα亚基的内在GTPase活性来调节配体诱导信号的水平和持续时间,从而使无活性的结合GDP的Gα重新形成。我们发现,即使在没有受体的情况下,RGS家族成员Sst2的突变(参考文献6-9)也能使酿酒酵母中的G蛋白偶联交配途径自发激活,其水平通常仅在存在配体时才可见。我们的工作证明了体内自发三聚体G蛋白信号的发生,并确定了RGS蛋白在防止这种不依赖受体的激活中的必要性。