GPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of Gs and Gq/11

Dayana Abboud, Adrian F. Daly, Nadine Dupuis, Mohamed Ali Bahri, Asuka Inoue, Andy Chevigné, Fabien Ectors, Alain Plenevaux, Bernard Pirotte, Albert Beckers () and Julien Hanson ()
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Dayana Abboud: University of Liège
Adrian F. Daly: University of Liège
Nadine Dupuis: University of Liège
Mohamed Ali Bahri: University of Liège
Asuka Inoue: Tohoku University
Andy Chevigné: Luxembourg Institute of Health
Fabien Ectors: Liège University
Alain Plenevaux: University of Liège
Bernard Pirotte: University of Liège
Albert Beckers: University of Liège
Julien Hanson: University of Liège

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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 (GhrhrGpr101). Here, we report that Gpr101 causes elevated GH/prolactin secretion in transgenic GhrhrGpr101 mice but without hyperplasia/tumorigenesis. We show that GPR101 constitutively activates not only Gs, but also Gq/11 and G12/13, 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.

Date: 2020
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DOI: 10.1038/s41467-020-18500-x

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