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^Gpr101). Here, we report that Gpr101 causes elevated GH/prolactin secretion in transgenic Ghrhr^Gpr101 mice but without hyperplasia/tumorigenesis. We show that GPR101 constitutively activates not only G_s, but also G_q/11 and G_12/13, 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，过度分泌 GH 会导致巨人症。一种形式是 X-linked acrogigantism (X-LAG)，其中婴儿会出现分泌 GH 的垂体肿瘤，过度表达孤儿 G 蛋白偶联受体 GPR101。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、人类肿瘤和由大鼠Ghrhr启动子 ( Ghr ^Gpr101 )驱动的生长激素 Gpr101 表达升高的转基因小鼠中的作用。在这里，我们报告 Gpr101 导致转基因Ghrhr ^Gpr101小鼠的GH/催乳素分泌升高，但没有增生/肿瘤发生。我们表明 GPR101 不仅组成性激活 G_s，还有 G _q/11和 G _12/13，这会导致 GH 分泌而不是增殖。GPR101 信号传导的这些特征，特别是 PKC 激活，也存在于具有高 GPR101 表达的人类垂体肿瘤中。这些结果强调了 GPR101 在调节生长激素轴功能中的作用。