Unacylated ghrelin is not a functional antagonist but a full agonist of the type 1a growth hormone secretagogue receptor (GHS-R)

Mol Cell Endocrinol. 2007 Aug 15;274(1-2):30-4. doi: 10.1016/j.mce.2007.05.010. Epub 2007 May 21.


Recent findings demonstrate that the effects of ghrelin can be abrogated by co-administered unacylated ghrelin (UAG). Since the general consensus is that UAG does not interact with the type 1a growth hormone secretagogue receptor (GHS-R), a possible mechanism of action for this antagonistic effect is via another receptor. However, functional antagonism of the GHS-R by UAG has not been explored extensively. In this study we used human GHS-R and aequorin expressing CHO-K1 cells to measure [Ca(2+)](i) following treatment with UAG. UAG at up to 10(-5)M did not antagonize ghrelin induced [Ca(2+)](i). However, UAG was found to be a full agonist of the GHS-R with an EC(50) of between 1.6 and 2 microM using this in vitro system. Correspondingly, UAG displaced radio-labeled ghrelin from the GHS-R with an IC(50) of 13 microM. In addition, GHS-R antagonists were found to block UAG induced [Ca(2+)](i) with approximately similar potency to their effect on ghrelin activation of the GHS-R, suggesting a similar mode of action. These findings demonstrate in a defined system that UAG does not antagonize activation of the GHS-R by ghrelin. But our findings also emphasize the importance of assessing the concentration of UAG used in both in vitro and in vivo experimental systems that are aimed at examining GHS-R independent effects. Where local concentrations of UAG may reach the high nanomolar to micromolar range, assignment of GHS-R independent effects should be made with caution.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Ghrelin
  • Glucagon / metabolism
  • Humans
  • Peptide Hormones / chemistry
  • Peptide Hormones / metabolism*
  • Peptides / metabolism
  • Radioligand Assay
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Ghrelin
  • Somatostatin / metabolism


  • Ghrelin
  • Peptide Hormones
  • Peptides
  • Receptors, G-Protein-Coupled
  • Receptors, Ghrelin
  • obestatin, human
  • Somatostatin
  • Glucagon