Scheschonka A, Dessauer C W, Sinnarajah S, Chidiac P, Shi C S, Kehrl J H
B Cell Molecular Biology Section, Laboratory Immunoregulation, National Institutes of Health, Bethesda, Maryland 20892, USA.
Mol Pharmacol. 2000 Oct;58(4):719-28. doi: 10.1124/mol.58.4.719.
Many Regulators of G protein Signaling (RGS) proteins accelerate the intrinsic GTPase activity of G(ialpha) and G(qalpha)-subunits [i.e., behave as GTPase-activating proteins (GAPs)] and several act as G(qalpha)-effector antagonists. RGS3, a structurally distinct RGS member with a unique N-terminal domain and a C-terminal RGS domain, and an N-terminally truncated version of RGS3 (RGS3CT) both stimulated the GTPase activity of G(ialpha) (except G(zalpha)) and G(qalpha) but not that of G(salpha) or G(12alpha). RGS3 and RGS3CT had G(qalpha) GAP activity similar to that of RGS4. RGS3 impaired signaling through G(q)-linked receptors, although RGS3CT invariably inhibited better than did full-length RGS3. RGS3 potently inhibited G(qalpha)Q209L- and G(11alpha)Q209L-mediated activation of a cAMP-response element-binding protein reporter gene and G(qalpha)Q209L induced inositol phosphate production, suggesting that RGS3 efficiently blocks G(qalpha) from activating its downstream effector phospholipase C-beta. Whereas RGS2 and to a lesser extent RGS10 also inhibited signaling by these GTPase-deficient G proteins, other RGS proteins including RGS4 did not. Mutation of residues in RGS3 similar to those required for RGS4 G(ialpha) GAP activity, as well as several residues N terminal to its RGS domain impaired RGS3 function. A greater percentage of RGS3CT localized at the cell membrane than the full-length version, potentially explaining why RGS3CT blocked signaling better than did full-length RGS3. Thus, RGS3 can impair Gi- (but not Gz-) and Gq-mediated signaling in hematopoietic and other cell types by acting as a GAP for G(ialpha) and G(qalpha) subfamily members and as a potent G(qalpha) subfamily effector antagonist.
许多G蛋白信号调节因子（RGS）蛋白可加速G（ialpha）和G（qalpha）亚基的内在GTP酶活性[即表现为GTP酶激活蛋白（GAP）]，还有几种RGS蛋白可作为G（qalpha）效应拮抗剂。RGS3是一种结构独特的RGS成员，具有独特的N端结构域和C端RGS结构域，RGS3的N端截短版本（RGS3CT）均能刺激G（ialpha）（G（zalpha）除外）和G（qalpha）的GTP酶活性，但不能刺激G（salpha）或G（12alpha）的GTP酶活性。RGS3和RGS3CT具有与RGS4相似的G（qalpha）GAP活性。RGS3会损害通过G（q）偶联受体的信号传导，尽管RGS3CT始终比全长RGS3具有更好的抑制作用。RGS3强烈抑制G（qalpha）Q209L和G（11alpha）Q209L介导的cAMP反应元件结合蛋白报告基因的激活以及G（qalpha）Q209L诱导的肌醇磷酸生成，这表明RGS3能有效阻止G（qalpha）激活其下游效应物磷脂酶C-β。虽然RGS2以及程度较轻的RGS10也能抑制这些GTP酶缺陷型G蛋白的信号传导，但包括RGS4在内的其他RGS蛋白则不能。RGS3中与RGS4 G（ialpha）GAP活性所需残基相似的残基发生突变，以及其RGS结构域N端的几个残基发生突变，都会损害RGS3的功能。与全长版本相比，更大比例的RGS3CT定位于细胞膜，这可能解释了为什么RGS3CT比全长RGS3能更好地阻断信号传导。因此，RGS3可通过作为G（ialpha）和G（qalpha）亚家族成员的GAP以及强效的G（qalpha）亚家族效应拮抗剂，损害造血细胞和其他细胞类型中Gi-（但不包括Gz-）和Gq介导的信号传导。
