BACKGROUND:GPCRs (G-protein-coupled receptors) play a central role in the regulation of smooth muscle cell (SMC) contractility, but the function of SMC-expressed orphan GPCR class C group 5 member C (GPRC5C) is unclear.OBJECTIVE:The aim of this project is to define the role of GPRC5C in SMC in vitro and in vivo.METHODS AND RESULTS:We studied the role of GPRC5C in the regulation of SMC contractility and differentiation in human and murine SMC in vitro, as well as in tamoxifen-inducible, SMC-specific GPRC5C knockout mice under basal conditions and in vascular disease in vivo. Mesenteric arteries from tamoxifen-inducible, SMC-specific GPRC5C knockout mice showed ex vivo significantly reduced angiotensin II (Ang II)–dependent calcium mobilization and contraction, whereas responses to other relaxant or contractile factors were normal. In vitro, the knockdown of GPRC5C in human aortic SMC resulted in diminished Ang II-dependent inositol phosphate production and lower myosin light chain phosphorylation. In line with this, tamoxifen-inducible, SMC-specific GPRC5C knockout mice showed reduced Ang II–induced arterial hypertension, and acute inactivation of GPRC5C was able to ameliorate established arterial hypertension. Mechanistically, we show that GPRC5C and the Ang II receptor AT1 dimerize, and knockdown of GPRC5C resulted in reduced binding of Ang II to AT1 receptors in HEK293 cells, human and murine SMC, and arteries from tamoxifen-inducible, SMC-specific GPRC5C knockout mice.CONCLUSIONS:Our data show that GPRC5C regulates Ang II-dependent vascular contraction by facilitating AT1 receptor-ligand binding and signaling.

中文翻译：

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孤儿 GPCR GPRC5C 促进血管紧张素 II 诱导的平滑肌收缩

背景：GPCR（G蛋白偶联受体）在平滑肌细胞（SMC）收缩性的调节中发挥核心作用，但SMC表达的孤儿GPCR C类5成员C（GPRC5C）的功能尚不清楚。本项目的目的是明确 GPRC5C 在体外和体内 SMC 中的作用。 方法和结果：我们在体外和小鼠 SMC 中研究了 GPRC5C 在调节 SMC 收缩性和分化中的作用，以及在基础条件下和体内血管疾病中他莫昔芬诱导的 SMC 特异性 GPRC5C 敲除小鼠。他莫昔芬诱导的 SMC 特异性 GPRC5C 敲除小鼠的肠系膜动脉在体外显着降低了血管紧张素 II (Ang II) 依赖性钙动员和收缩，而对其他松弛或收缩因子的反应正常。在体外，人主动脉 SMC 中 GPRC5C 的敲低导致 Ang II 依赖性磷酸肌醇产生减少和肌球蛋白轻链磷酸化降低。与此相一致的是，他莫昔芬诱导的、SMC特异性的GPRC5C敲除小鼠表现出Ang II诱导的动脉高血压减少，并且GPRC5C的急性失活能够改善已形成的动脉高血压。从机制上讲，我们发现 GPRC5C 和 Ang II 受体 AT1 二聚化，并且 GPRC5C 的敲除导致 HEK293 细胞、人和鼠 SMC 以及他莫昔芬诱导的 SMC 特异性 GPRC5C 敲除小鼠的动脉中 Ang II 与 AT1 受体的结合减少结论：我们的数据表明，GPRC5C 通过促进 AT1 受体-配体结合和信号传导来调节 Ang II 依赖性血管收缩。