Differential coupling of Arg- and Gly389 polymorphic forms of the beta1-adrenergic receptor leads to pathogenic cardiac gene regulatory programs.
Differential coupling of Arg- and Gly389 polymorphic forms of the beta1-adrenergic receptor leads to pathogenic cardiac gene regulatory programs.
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β1-肾上腺素能受体的 Arg- 和 Gly389 多态性的差异耦合导致致病性心脏基因调控程序。
DOI：
10.1152/physiolgenomics.90225.2008
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发表时间：
2008
影响因子：
4.6
通讯作者：
Liggett,StephenB
中科院分区：
文献类型：
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作者：
Swift,StevenM;Gaume,BrigitteR;Small,KerstenM;Aronow,BruceJ;Liggett,StephenB
β1-肾上腺素能受体（β1AR; ADRB1）多态性Arg389Gly位于细胞内环，与不同的人和小鼠心血管表型相关。为了验证β1-Arg389和β1-Gly389等位基因可以不同地偶联到经典的gs -腺苷酸环化酶(AC)/cAMP信号通路以外的途径，我们对野生型和转基因小鼠的心脏进行了比较基因表达谱分析，这些小鼠在发病前的早期年龄取样，表达人类β1-Arg389或β1-Gly389受体或AC5。这三种模型都上调了与RNA代谢和翻译相关的基因的表达，下调了与线粒体和能量代谢相关的基因的表达，这与camp驱动的心脏收缩力、蛋白质合成和线粒体能量产生的代偿性下调一致。两个β1AR等位基因都激活了与其他途径相关的额外基因。独特的是，β1-Arg389心脏表现出与炎症、程序性细胞死亡和细胞外基质相关基因的上调表达。这些观察结果扩大了7-跨膜结构域受体信号传导的范围，超出了已知的同源G蛋白偶联。此外，它们暗示了心脏β1AR中单个氨基酸变异所引起的一系列过程的改变，这可能被用于基因型特异性心力衰竭的诊断和治疗。
The β1-adrenergic receptor (β1AR; ADRB1) polymorphism Arg389Gly is located in an intracellular loop and is associated with distinct human and mouse cardiovascular phenotypes. To test the hypothesis that β1-Arg389 and β1-Gly389 alleles could differentially couple to pathways beyond that of classic Gs-adenylyl cyclase (AC)/cAMP signaling, we performed comparative gene expression profile analyses on hearts from wild-type and transgenic mice that expressed either human β1-Arg389 or β1-Gly389 receptors, or AC5, sampling at an early age prior to the onset of pathological features. All three models upregulated the expression of genes associated with RNA metabolism and translation and downregulated genes associated with mitochondria and energy metabolism, consistent with shared cAMP-driven increase in cardiac contractility, protein synthesis, and compensatory downregulation of mitochondrial energy production. Both β1AR alleles activated additional genes associated with other pathways. Uniquely, β1-Arg389 hearts exhibited upregulated expression of genes associated with inflammation, programmed cell death, and extracellular matrix. These observations expand the scope of 7-transmembrane domain receptor signaling propagation beyond known cognate G protein couplings. Moreover, they implicate alterations of a repertoire of processes evoked by a single amino acid variation in the cardiac β1AR that might be exploited for genotype-specific heart failure diagnostics and therapeutics.