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首页> 外文期刊>American Journal of Physiology >Human muscle-specific A-kinase anchoring protein polymorphisms modulate the susceptibility to cardiovascular diseases by altering cAMP/PKA signaling
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Human muscle-specific A-kinase anchoring protein polymorphisms modulate the susceptibility to cardiovascular diseases by altering cAMP/PKA signaling

机译：人体肌肉特异性A-激酶锚定蛋白质多态性通过改变CAMP / PKA信号传导来调节对心血管疾病的敏感性

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摘要

One of the crucial cardiac signaling pathways is cAMP-mediated PKA signal transduction, which is regulated by a family of scaffolding proteins, i.e., A-kinase anchoring proteins (AKAPs). Muscle-specific AKAP (mAKAP) partly regulates cardiac cAMP/PKA signaling by binding to PKA and phosphodies-terase 4D3 (PDE4D3), among other proteins, and plays a central role in modulating cardiac remodeling. Moreover, genetics plays an incomparable role in modifying the risk of cardiovascular diseases (CVDs). Single-nucleotide polymorphisms (SNPs) in various proteins have especially been shown to predispose individuals to CVDs. Hence, we hypothesized that human mAKAP polymorphisms found in humans with CVDs alter the cAMP/PKA pathway, influencing the susceptibility of individuals to CVDs. Our computational analyses revealed two mAKAP SNPs found in cardiac disease-related patients with the highest predicted deleterious effects, Ser 1653 Arg (S1653R) and Glu 2124 Gly (E2124G). Coimmunoprecipitation data in human embryonic kidney-293T cells showed that the S1653R SNP, present in the PDE4D3-binding domain of mAKAP, changed the binding of PDE4D3 to mAKAP and that the E2124G SNP, Hanking the 3'-PKA binding domain, changed the binding of PKA before and after stimulation with isoproterenol. These SNPs significantly altered intracel-lular cAMP levels, global PKA activity, and cytosolic PDE activity compared with the wild type before and after isoproterenol stimulation. PKA-mediated phosphorylation of pathological markers was found to be upregulated after cell stimulation in both mutants. In conclusion, human mAKAP polymorphisms may influence the propensity of developing CVDs by affecting cAMP/PKA signaling, supporting the clinical significance of PKA-mAKAP-PDE4D3 interactions.
机译：其中一个关键的心脏信号传导途径是阵营介导的PKA信号转导，其由一系列脚手架蛋白质，即A-kinase锚定蛋白（Akaps）调节。肌肉特异性akap（makap）通过与其他蛋白质中的pka和磷酸二胞嘧啶4d3（pde4d3）结合来分别调节心阵阵列/ pka信号传导，并在调节心脏重塑方面发挥重要作用。此外，遗传学在改变心血管疾病（CVDS）的风险方面发挥了无与伦比的作用。各种蛋白质中的单核苷酸多态性（SNP）尤其被证明使个体倾向于CVDS。因此，我们假设具有CVDS中的人体Makap多态性改变营地/ PKA途径，影响个体对CVDS的易感性。我们的计算分析显示，在心脏病相关患者中发现了两种Makap SNP，患有最高的有害效应，Ser 1653 Arg（S1653R）和Glu 2124 Gly（E2124G）。人胚胎肾-293T细胞中的CoimMunopropipipitipation数据表明，存在于MakaP的PDE4D3结合结构域的S1653R SNP改变了PDE4D3至MaCaP的结合，并且E2124G SNP，携带3'-PKA结合域，改变了结合PKA与异丙肾上腺素刺激前后。与异丙酚刺激之前和之后的野生型相比，这些SNP明显改变了胞内撞球阵列，全局PKA活性和细胞溶质PDE活性。发现PKA介导的病理标志物的磷酸化在两个突变体中的细胞刺激后上调。总之，人maCaP多态性可能影响CAMP / PKA信号传导来影响显CVDS的倾向，支持PKA-MAKAP-PDE4D3相互作用的临床意义。

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