ESPE Abstracts (2014) 82 FC8.5

INSERM, Université Paris Descartes, UMR-S 894, Centre de Psychiatrie and Neurosciences, Paris, France


Background: The deciphering of the physiological importance of the GH secretagogue receptor (Ghsr), a G protein-coupled receptor (GPCR) depicted as the sole receptor of the pleiotropic hormone ghrelin, was initially compromised by the modest phenotype observed in Ghsr−/− animals. This lack of a robust response to total loss of Ghsr may result from developmental compensatory signals. Still, the description of rare mutations in the GHSR partially affecting receptor function in patients with short stature or partial GH-deficiency allowed us to ascertain its role in somatic growth.

Objective and Hypotheses: We hypothesized that a recently generated line of rats carrying a premature termination codon in the Ghsr gene (Q343X) might be an ideal model to explore Ghsr physiology.

Method: The mechanism of action of this specific mutation was deciphered using HEK293 cells.

Results: The Q343X mutation does not impair cell surface expression of Ghsr. The functional analysis of this GPCR in calcium flux experiments revealed that, compared to the WT isoform, the mutant isoform has an increased potency as well as a major increase of the maximal response in the presence of increasing concentrations of ghrelin (EC50=2.1±0.4 and 0.6±0.1 nM; Emax=26±1 and 39±1% respectively, mean±S.E.M., n=3). Similar patterns of response were also found in reporter gene assays depicting the serum-response elements (SRE) or cAMP-response elements (CRE) pathways. Of note, when subjected to a maximal dose of ghrelin, internalization of the mutated receptor is blunted compared to the WT receptor.

Conclusion: These in vitro observations are supportive of a gain-of-function associated to the Ghsr Q343X mutant allele. Interestingly, our very first in vivo data are consistent with an increased body weight and chow intake in adult rats carrying the mutated allele. This model therefore deserves an extensive phenotypic evaluation.

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