Dysregulation of cardiac signaling in disease and stress

项目摘要 G蛋白偶联受体2(GRK2)是G蛋白偶联受体循环和脱敏的关键调节因子 这在包括肥厚和心力衰竭(HF)在内的几种心脏病理中都被上调。心脏 缺血再灌注损伤诱导ERK介导的GRK2在S670的磷酸化，从而导致 GRK2从胞浆到线粒体的移位。我们发现在成年心肌细胞中 线粒体GRK2通过抑制丙酮酸调节葡萄糖介导的氧化磷酸化 脱氢酶，葡萄糖氧化的限速酶。尽管线粒体的生理影响 GRK2已有报道，但目前尚不清楚线粒体GRK2是如何调节心肌线粒体的 新陈代谢。这一建议的重点是从机制上破译GRK2磷酸化和GRK2是如何 线粒体易位调节心脏葡萄糖代谢。此外，我们提出线粒体 GRK2作为心肌梗死后关键代谢信号的增强子参与心肌梗死后的信号传导 上睑下垂-一种新的溶解细胞死亡机制。因此，我们假设S670处的GRK2磷酸化是 对于改变代谢可获得性和心脏损伤导致的心肌细胞反应至关重要。 利用一个新的GRK-S670A和两个Gasdermin E小鼠模型，我们提出了两个具体的目标：1) 确定mitoGRK2如何调节心肌线粒体代谢；评估磷酸化是否 S670处的GRK2调节心脏焦磷酸信号。总体而言，我们的工作将阐明GRK2的作用 心肌细胞S670的磷酸化及其翻译后修饰如何调节代谢 信号和慢性损伤反应。这项研究的首要目标是开发新的机械原理 开发和鉴定治疗心力衰竭的新药的信号。

Project Summary G-protein coupled receptor (GPCR) kinase-2 (GRK2) is a key regulator of GPCR recycling and desensitization that is upregulated in several cardiac pathologies, including hypertrophy and heart failure (HF). Cardiac ischemia-reperfusion injury induces ERK-mediated phosphorylation of GRK2 at S670, which results in the translocation of GRK2 from the cytosol to mitochondria. We discovered that in the adult cardiomyocyte mitochondrial GRK2 regulates glucose-mediated oxidative phosphorylation by inhibiting pyruvate dehydrogenase, the rate limiting enzyme of glucose oxidation. Although the physiological impact of mitochondrial GRK2 was reported, it remains largely unknown how mitochondrial GRK2 regulates cardiac mitochondrial metabolism. This proposal focuses on deciphering mechanistically how GRK2 phosphorylation and mitochondrial translocation regulate cardiac glucose metabolism. Additionally, we propose that mitochondrial GRK2 participates in key metabolic signaling post-myocardial infarction (MI) by acting as an amplifier of pyroptosis- a novel lytic cell death mechanism. Thus, we hypothesize that GRK2 phosphorylation at S670 is paramount for cardiomyocyte responses in consequence of altering metabolic availability and cardiac injury. Using a novel GRK-S670A and two Gasdermin E mouse models, we propose to carry out two specific aims: 1.) Determine how mitoGRK2 regulates cardiac mitochondrial metabolism; 2.) Assess whether phosphorylation of GRK2 at S670 modulates cardiac pyroptotic signaling. Overall, our work will shed light on the role of GRK2 phosphorylation at S670 in cardiomyocytes and how this post-translational modification regulates metabolic signaling and chronic-injury responses. The overarching goal of this research is to exploit novel mechanistic signaling for the development and identification of new pharmaceutical drugs for HF treatment.