Regulation of cardiomyocyte signaling by RGS proteins: Differential selectivity towards G proteins and susceptibility to regulation
Regulation of cardiomyocyte signaling by RGS proteins: Differential selectivity towards G proteins and susceptibility to regulation
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DOI：
10.1016/j.yjmcc.2006.04.003
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发表时间：
2006-07-01
影响因子：
5
通讯作者：
Mende, Ulrike
中科院分区：
文献类型：
--
作者：
Hao, Jianming;Michalek, Christina;Mende, Ulrike
许多调节心肌细胞生长、分化和功能的信号都是通过异源三聚体G蛋白介导的，而G蛋白受RGS蛋白（regulatory of G protein Signaling）的控制。几种RGS蛋白在心脏中表达，但迄今为止对它们的功能和调控知之甚少。利用腺病毒基因转移，我们首次全面分析了主要心脏RGS蛋白（RGS2-RGS5）调节成人心室肌细胞（AVM）中枢G蛋白介导的信号通路的能力和选择性。所有四种RGS蛋白都能有效抑制G（q/11）介导的磷脂酶C β刺激和细胞生长（在新生儿肌细胞中评估）。重要的是，RGS2选择性地抑制G（q/11）信号，而RGS3、RGS4和RGS5具有调节G（q/11）和G（i/o）信号（碳甾醇诱导的cAMP抑制）的能力。G，信号传导不受影响，并且，与其他细胞系的报道相反，RGS2-RGS5似乎不直接调节AVM中的腺苷酸环化酶。由于RGS蛋白的表达可以受到许多不同刺激的高度调控，我们也验证了RGS表达在AVM中受G蛋白介导的调控的假设，并确定了G蛋白信号增强改变内源性RGS在AVM中的表达的特异性。RGS2 mRNA和蛋白可通过G（q/11）信号((α 1)-肾上腺素能刺激或G α （*)(q)过表达）的增强而显着但短暂上调，可能通过负反馈机制。相比之下，G（q/11）信号的其他负调控因子（RGS3-RGS5）没有变化。内源性RGS2（而非RGS3-RGS5）的表达在AC信号（β -肾上腺素或forskolin刺激）增强的细胞中也上调。综上所述，这些发现表明RGS蛋白在调节肌细胞信号传导中的不同作用。RGS2是唯一的选择性和高度调控的G（q/11）信号抑制剂，可能成为改善G（q/11）介导的信号传导和生长的有希望的靶点。(c) 2006爱思唯尔公司版权所有。
Many signals that regulate cardiomyocyte growth, differentiation and function are mediated via heterotrimeric G proteins, which are under the control of RGS proteins (Regulators of G protein Signaling). Several RGS proteins are expressed in the heart, but so far little is known about their function and regulation. Using adenoviral gene transfer, we conducted the first comprehensive analysis of the capacity and selectivity of the major cardiac RGS proteins (RGS2-RGS5) to regulate central G protein-mediated signaling pathways in adult ventricular myocytes (AVM). All four RGS proteins potently inhibited G(q/11)-mediated phospholipase C beta stimulation and cell growth (assessed in neonatal myocytes). Importantly, RGS2 selectively inhibited G(q/11) signaling, whereas RGS3, RGS4 and RGS5 had the capacity to regulate both G(q/11) and G(i/o) signaling (carbachol-induced cAMP inhibition). G, signaling was unaffected, and, contrary to reports in other cell lines, RGS2-RGS5 did not appear to regulate adenylate cyclase directly in AVM. Since RGS proteins can be highly regulated in their expression by many different stimuli, we also tested the hypothesis that RGS expression is subject to G protein-mediated regulation in AVM and determined the specificity with which enhanced G protein signaling alters endogenous RGS expression in AVM. RGS2 mRNA and protein were markedly but transiently up-regulated by enhanced G(q/11) signaling ((alpha 1)-adrenergic stimulation or G alpha(*)(q) overexpression), possibly by a negative feedback mechanism. In contrast, the other negative regulators of G(q/11) signaling (RGS3-RGS5) were unchanged. Endogenous RGS2 (but not RGS3-RGS5) expression was also up-regulated in cells with enhanced AC signaling (beta-adrenergic or forskolin stimulation). Taken together, these findings suggest diverse roles of RGS proteins in regulating myocyte signaling. RGS2 emerged as the only selective and highly regulated inhibitor of G(q/11) signaling that could potentially become a promising target for ameliorating G(q/11)-mediated signaling and growth. (c) 2006 Elsevier Inc. All rights reserved.