title: Unacylated ghrelin is not a functional antagonist but a full agonist of the type 1a growth hormone secretagogue receptor (GHS-R).
abstract: 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.
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Gauna
authors.forename: Bedette
authors.initials: B
authors.lastname: van de Zande
authors.forename: Anke
authors.initials: A
authors.lastname: van Kerkwijk
authors.forename: Axel P N
authors.initials: AP
authors.lastname: Themmen
authors.forename: A J
authors.initials: AJ
authors.lastname: van der Lely
authors.forename: Patric J D
authors.initials: PJ
authors.lastname: Delhanty
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D054439:Ghrelin; D005934:Glucagon / Q000378:metabolism; D006801:Humans; D036361:Peptide Hormones / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D011869:Radioligand Assay; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054440:Receptors, Ghrelin; D013004:Somatostatin / Q000378:metabolism
chemical_list: D054439:Ghrelin; D036361:Peptide Hormones; D010455:Peptides; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; C505799:obestatin, human; D013004:Somatostatin; D005934:Glucagon