ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 P432

GHRH as a possible allosteric ligand of the ghrelin receptor GHS-R1a

Marcos C Carreira, Jesus P Camiña, Mary Lage & Felipe F Casanueva

CIBER Fisiopatología de la Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III. Área de Investigación, Complejo Hospitalario Universitario de Santiago, Universidade de Santiago de Compostela, Santiago de Compostela, Spain.

Ghrelin and GHRH are two hormones involved in the growth hormone (GH) secretion through their respective receptors. The growth hormone secretagogue receptor subtype 1a (GHS-R1a) is involved in biological actions exerted by ghrelin triggering intracellular second messengers coupled to Gαq/11 protein. In this work, we analyzed the possible interaction between GHRH and GHS-R1a as well as the subsequent intracellular pathways. The results showed that GHRH induced, in a dose-dependent manner, a calcium mobilization from intracellular stores followed by a calcium influx through calcium channels at plasma membrane in HEK 293 cells stably transfected with GHS-R1a (HEK-GHSR1a), an effect that was not observed in untransfected HEK 293 cells. Radioligand binding and cross-linking studies revealed that GHRH-mediated response on calcium signal was mediated by GHS-R1a, showing that the presence of GHRH increased the binding capacity of 125I-ghrelin. The administration of GHRH stimulated the activation of the IP3 signalling pathway. Interestingly, GHRH potentiated ghrelin-induced IP3 mobilization. In addition, confocal microscopy in CHO cells transfected with GHS-R1a tagged EGFP showed that GHRH was able to induce the GHS-R1a endocytosis. In conclusion GHRH is able to activate the GHS-R1a inducing an increase both in the ghrelin binding capacity and intracellular response. The regulation of the ghrelin-mediated signaling by GHRH could have implications in the GH secretion and could be an explanation of the observed synergistic effect of ghrelin and GHRH on GH secretion.

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