Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a

Felipe F. Casanueva, Jesus P. Camiña, Marcos C. Carreira, Yolanda Pazos, Jozsef L. Varga, Andrew V Schally

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Ghrelin synergizes with growth hormone-releasing hormone (GHRH) to potentiate growth hormone (GH) response through a mechanism not yet fully characterized. This study was conducted to analyze the role of GHRH as a potential ligand of the ghrelin receptor, GHS-R1a. The results show that hGHRH(1-29)NH2 (GHRH) induces a dose-dependent calcium mobilization in HEK 293 cells stably transfected with GHS-R1a an effect not observed in wildtype HEK 293 cells. This calcium rise is also observed using the GHRH receptor agonists JI-34 and JI-36. Radioligand binding and cross-linking studies revealed that calcium response to GHRH is mediated by the ghrelin receptor GHS-R1a. GHRH activates the signaling route of inositol phosphate and potentiates the maximal response to ghrelin measured in inositol phosphate turnover. The presence of GHRH increases the binding capacity of 125I-ghrelin in a dose dependent-fashion showing a positive binding cooperativity. In addition, confocal microscopy in CHO cells transfected with GHS-R1a tagged with enhanced green fluorescent protein shows that GHRH activates the GHS-R1a endocytosis. Furthermore, the selective GHRH-R antagonists, JV-1-42 and JMR-132, act also as antagonists of the ghrelin receptor GHS-R1a. Our findings suggest that GHRH interacts with ghrelin receptor GHS-R1a, and, in consequence, modifies the ghrelin-associated intracellular signaling pathway. This interaction may represent a form of regulation, which could play a putative role in the physiology of GH regulation and appetite control.

Original languageEnglish
Pages (from-to)20452-20457
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number51
DOIs
StatePublished - Dec 23 2008

Fingerprint

Ghrelin Receptor
Growth Hormone-Releasing Hormone
Ghrelin
Inositol Phosphates
HEK293 Cells
Calcium
Growth Hormone
Sermorelin
Hormone Antagonists
Appetite Regulation
CHO Cells
Endocytosis
Confocal Microscopy
Hormones
Ligands

Keywords

  • Ghrelin
  • Ghrelin receptor
  • GHRH

ASJC Scopus subject areas

  • General

Cite this

Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a. / Casanueva, Felipe F.; Camiña, Jesus P.; Carreira, Marcos C.; Pazos, Yolanda; Varga, Jozsef L.; Schally, Andrew V.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 51, 23.12.2008, p. 20452-20457.

Research output: Contribution to journalArticle

Casanueva, Felipe F. ; Camiña, Jesus P. ; Carreira, Marcos C. ; Pazos, Yolanda ; Varga, Jozsef L. ; Schally, Andrew V. / Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 51. pp. 20452-20457.
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AB - Ghrelin synergizes with growth hormone-releasing hormone (GHRH) to potentiate growth hormone (GH) response through a mechanism not yet fully characterized. This study was conducted to analyze the role of GHRH as a potential ligand of the ghrelin receptor, GHS-R1a. The results show that hGHRH(1-29)NH2 (GHRH) induces a dose-dependent calcium mobilization in HEK 293 cells stably transfected with GHS-R1a an effect not observed in wildtype HEK 293 cells. This calcium rise is also observed using the GHRH receptor agonists JI-34 and JI-36. Radioligand binding and cross-linking studies revealed that calcium response to GHRH is mediated by the ghrelin receptor GHS-R1a. GHRH activates the signaling route of inositol phosphate and potentiates the maximal response to ghrelin measured in inositol phosphate turnover. The presence of GHRH increases the binding capacity of 125I-ghrelin in a dose dependent-fashion showing a positive binding cooperativity. In addition, confocal microscopy in CHO cells transfected with GHS-R1a tagged with enhanced green fluorescent protein shows that GHRH activates the GHS-R1a endocytosis. Furthermore, the selective GHRH-R antagonists, JV-1-42 and JMR-132, act also as antagonists of the ghrelin receptor GHS-R1a. Our findings suggest that GHRH interacts with ghrelin receptor GHS-R1a, and, in consequence, modifies the ghrelin-associated intracellular signaling pathway. This interaction may represent a form of regulation, which could play a putative role in the physiology of GH regulation and appetite control.

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