From the Departments of Pharmacology and.
Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota 55455 and.
J Biol Chem. 2018 Jun 8;293(23):8734-8749. doi: 10.1074/jbc.RA118.002283. Epub 2018 Apr 2.
G protein-coupled receptors that signal through Gα (G receptors), such as α-adrenergic receptors (α-ARs) or angiotensin receptors, share a common proximal signaling pathway that activates phospholipase Cβ1 (PLCβ1), which cleaves phosphatidylinositol 4,5-bisphosphate (PIP) to produce inositol 1,4,5-trisphosphate (IP) and diacylglycerol. Despite these common proximal signaling mechanisms, G receptors produce distinct physiological responses, yet the mechanistic basis for this remains unclear. In the heart, G receptors are thought to induce myocyte hypertrophy through a mechanism termed excitation-transcription coupling, which provides a mechanistic basis for compartmentalization of calcium required for contraction IP-dependent intranuclear calcium required for hypertrophy. Here, we identified subcellular compartmentalization of G-receptor signaling as a mechanistic basis for unique G receptor-induced hypertrophic phenotypes in cardiac myocytes. We show that α-ARs co-localize with PLCβ1 and PIP at the nuclear membrane. Further, nuclear α-ARs induced intranuclear PLCβ1 activity, leading to histone deacetylase 5 (HDAC5) export and a robust transcriptional response ( significant up- or down-regulation of 806 genes). Conversely, we found that angiotensin receptors localize to the sarcolemma and induce sarcolemmal PLCβ1 activity, but fail to promote HDAC5 nuclear export, while producing a transcriptional response that is mostly a subset of α-AR-induced transcription. In summary, these results link G-receptor compartmentalization in cardiac myocytes to unique hypertrophic transcription. They suggest a new model of excitation-transcription coupling in adult cardiac myocytes that accounts for differential G-receptor localization and better explains distinct physiological functions of G receptors.
G 蛋白偶联受体通过 Gα（G 受体）信号传导，如α-肾上腺素能受体（α-ARs）或血管紧张素受体，它们共享一个共同的近端信号通路，该通路激活磷脂酶 Cβ1（PLCβ1），后者将磷脂酰肌醇 4,5-二磷酸（PIP）切割成肌醇 1,4,5-三磷酸（IP）和二酰基甘油。尽管这些共同的近端信号传导机制，G 受体产生不同的生理反应，但这种机制基础仍不清楚。在心脏中，G 受体被认为通过一种称为兴奋转录偶联的机制诱导心肌细胞肥大，这为收缩所需的钙离子的区室化提供了机制基础 IP 依赖性核内钙离子对于肥大。在这里，我们确定了 G 受体信号传导的亚细胞区室化作为 G 受体诱导心肌细胞肥大表型独特的机制基础。我们发现 α-ARs 与 PLCβ1 和 PIP 一起定位于核膜。此外，核 α-ARs 诱导核内 PLCβ1 活性，导致组蛋白去乙酰化酶 5（HDAC5）输出和强大的转录反应（806 个基因的显著上调或下调）。相反，我们发现血管紧张素受体定位于肌膜并诱导肌膜 PLCβ1 活性，但不能促进 HDAC5 核输出，而产生的转录反应主要是 α-AR 诱导转录的子集。总之，这些结果将心肌细胞中的 G 受体区室化与独特的肥大转录联系起来。它们提出了一种新的成年心肌细胞兴奋转录偶联模型，该模型解释了 G 受体的不同定位，并更好地解释了 G 受体的不同生理功能。
