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Accueil > Bibliographie > Ghrelin receptor (GHS-R1a) and its constitutive activity in somatotroph (...)

Ghrelin receptor (GHS-R1a) and its constitutive (...)

J Clin Endocrinol Metab. 2014 Oct ; [Epub ahead of print]
Ghrelin receptor (GHS-R1a) and its constitutive activity in somatotroph adenomas : a new co-targeting therapy using GHS-R1a inverse agonists and somatostatin analogs.
Mear Y, Blanchard MP, Defilles C, Brue T, Figarella-Branger D, Graillon T, Manavela M, Barlier A, Enjalbert A, Thirion S.

Context : The ghrelin receptor GHS-R1a, is highly expressed in human somatotroph adenomas and exhibits unusual high basal signaling activity. In humans, the suppression of this constitutive activity by mutation induces a short stature. Objective : Using a GHS-R1a inverse agonist, MSP, we explored the role of GHS-R1a constitutive activity in GH hypersecretion from somatotroph adenomas and as putative therapeutic target. Design : The effects of MSP were assessed on GH secretion from 19 human somatotroph tumors in vitro. Moreover, these effects were compared with those of octreotide (sst2 agonist) and with the combination of both drugs. Expression and localization of GHS-R1a and sst2 were studied. Results : For all tumors, MSP inhibited GH secretion in a dose dependent manner, from 13 to 64%. Moreover, MSP enhanced octreotide-induced GH inhibition. For 5 tumors, the effects of combined MSP + octreotide treatment were significantly higher than the sum of effects of each drug alone. MSP increased the membrane localization of GHS-R1a and of microdomains colocalizing sst2-GHS-R1a, highlighting the cooperation between the two drugs. Conclusions : The GHS-R1a inverse agonist could open new therapeutic options for acromegalic patients, particularly patients partially sensitive to octreotide whose GH secretion is not completely controlled by the sst2 agonist.


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