The G‐protein‐coupled receptor, endothelin receptor B (EDNRB), is an important regulator of melanocyte survival and proliferation. It acts by stimulating downstream heterotrimeric G proteins, such as Gα_q and Gα₁. Constitutively active, oncogenic versions of Gα_q and Gα₁₁ drive melanomagenesis, but the role of Ednrb in the context of these mutant G proteins has not been previously examined. In this paper, we used a knock‐in mouse allele at the Rosa26 locus to force oncogenic GNAQ^Q209L expression in melanocytes in combination with Ednrb gene knockout. The resulting pathological analysis revealed that every aspect of melanomagenesis driven by GNAQ^Q209L was inhibited. We conclude that even in the presence of oncogenic Gα_q, the Ednrb receptor activates normal Gα_q and Gα₁₁ proteins. This likely promotes tumorigenesis by activating phospholipase C‐beta, the immediate effector of Gα_q/11. These findings suggest that it might be possible to target upstream receptors to offset the effects of hyperactive G proteins, recognized as the cause of a growing number of human disorders.

中文翻译：

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内皮素信号促进由组成型活性 GNAQ 驱动的黑色素瘤发生。

G 蛋白偶联受体内皮素受体 B (EDNRB) 是黑素细胞存活和增殖的重要调节因子。它通过刺激下游异源三聚体 G 蛋白起作用，例如 Gα _q和 Gα ₁。Gα _q和 Gα _{11 的}组成型活性致癌版本驱动黑色素瘤发生，但之前尚未研究过 Ednrb 在这些突变 G 蛋白背景下的作用。在本文中，我们在Rosa26基因座使用敲入小鼠等位基因，结合Ednrb基因敲除，在黑素细胞中强制致癌 GNAQ ^Q209L表达。由此产生的病理分析表明，由 GNAQ 驱动的黑色素瘤发生的各个方面^Q209L被抑制。我们得出结论，即使存在致癌 Gα _q，Ednrb 受体也会激活正常的 Gα _q和 Gα ₁₁蛋白。这可能通过激活磷脂酶 C-β（Gα _q/11的直接效应物）来促进肿瘤发生。这些发现表明，有可能靶向上游受体来抵消过度活跃的 G 蛋白的影响，而 G 蛋白被认为是导致越来越多人类疾病的原因。