Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, Liège, Belgium.
Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Liège, Belgium.
Nat Commun. 2020 Sep 21;11(1):4752. doi: 10.1038/s41467-020-18500-x.
Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH-secreting pituitary tumors over-expressing the orphan G-protein coupled receptor, GPR101. The role of GPR101 in GH secretion remains obscure. We studied GPR101 signaling pathways and their effects in HEK293 and rat pituitary GH3 cell lines, human tumors and in transgenic mice with elevated somatotrope Gpr101 expression driven by the rat Ghrhr promoter (Ghrhr). Here, we report that Gpr101 causes elevated GH/prolactin secretion in transgenic Ghrhr mice but without hyperplasia/tumorigenesis. We show that GPR101 constitutively activates not only G, but also G and G, which leads to GH secretion but not proliferation. These signatures of GPR101 signaling, notably PKC activation, are also present in human pituitary tumors with high GPR101 expression. These results underline a role for GPR101 in the regulation of somatotrope axis function.
生长激素（GH）是生长的关键调节剂，GH 过度分泌可导致巨人症。其中一种形式是 X 连锁肢端巨大症（X-LAG），婴儿会在过度表达孤儿 G 蛋白偶联受体 GPR101 的情况下发展为分泌 GH 的垂体肿瘤。GPR101 在 GH 分泌中的作用仍不清楚。我们研究了 GPR101 信号通路及其在 HEK293 和大鼠垂体 GH3 细胞系、人类肿瘤以及由大鼠 Ghrhr 启动子（Ghrhr）驱动的升高的生长激素细胞 Gpr101 表达的转基因小鼠中的作用。在这里，我们报告 Gpr101 导致转基因 Ghrhr 小鼠中的 GH/催乳素分泌升高，但没有增生/肿瘤发生。我们表明 GPR101 不仅持续激活 G，还激活 G 和 G，这导致 GH 分泌而不是增殖。GPR101 信号的这些特征，特别是 PKC 激活，也存在于高表达 GPR101 的人类垂体肿瘤中。这些结果强调了 GPR101 在调节生长激素细胞轴功能中的作用。
