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Endocrine Abstracts (2017) 49 EP928 | DOI: 10.1530/endoabs.49.EP928

1Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of disease, University of Liege, Liege, Belgium; 2Department of Endocrinology, CHU of Liege, Domaine Universitaire du Sart-Tilman, Liege, Belgium; 3Laboratory of Medicinal Chemistry, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liege, Liege, Belgium.


GPR101 is an orphan G-protein coupled receptor with unknown ligand. In 2014, an international study clearly pointed to a strong association between this receptor and the X-linked acrogigantism (X-LAG) syndrome, which begins in childhood and causes the “tallest giants”. The children (carriers of the GPR101 duplication on the X chromosome) grow abnormally even before they are one year old, secrete phenomenal quantities of growth hormone, and develop pituitary adenomas that do not respond to current therapies. The mechanism by which GPR101 contributes to increased growth hormone secretion is currently not known. Nevertheless, the lack of mechanistic insight into the function of GPR101 precludes its validation as a drug target. This lack of knowledge on GPR101 is the consequence of the paucity of specific pharmacological/research tools currently available. Therefore, we propose to study GPR101 functions and its role in growth hormone regulation. First, we determined the receptor precise cellular localization and trafficking. We also deciphered its constitutive signalling pathways by detecting high cAMP levels as well as arrestin recruitment to GPR101. We completed our study with an examination of receptor coupling to other pathways and G proteins. In parallel, we screened small molecule libraries in order to identify GPR101 specific ligands, to establish the link between GPR101 and X-LAG with a pharmacological approach. Furthermore, we applied targeted mutagenesis to modulate the receptor constitutive activity in order to understand the receptor function at a molecular level. These GPR101 mutants will help us to understand the role of this receptor in GH regulation and/or to treat people suffering from pituitary dysfunction. This information is an absolute prerequisite to link molecular pharmacology of GPR101 with physiological functions.

Volume 49

19th European Congress of Endocrinology

Lisbon, Portugal
20 May 2017 - 23 May 2017

European Society of Endocrinology 

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