help button home button Endocrine Society Molecular Endocrinology ENDO 08 Sessions Library
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
This version published online on May 19, 2005
Molecular Endocrinology, doi:10.1210/me.2005-0059
A more recent version of this article appeared on September 1, 2005
This Article
Right arrow Author Manuscript (PDF)
Right arrow All Versions of this Article:
19/9/2400    most recent
Author Manuscript (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Holst, B.
Right arrow Articles by Schwartz, T. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Holst, B.
Right arrow Articles by Schwartz, T. W.

Submitted on January 25, 2005
Accepted on May 9, 2005

Non-peptide and Peptide Growth Hormone Secretagogues Act both as Ghrelin receptor Agonist and as Positive or Negative Allosteric Modulators of Ghrelin Signaling

Birgitte Holst*, Erik Brandt, Anders Bach, Anders Heding, and Thue W. Schwartz

Laboratory for Molecular Pharmacology, Department of Pharmacology, The Panum Institute. University of Copenhagen, Blegdamsvej 3, Copenhagen, 7TM Pharma A/S, Fremtidsvej 3, Hørsholm, Denmark

* To whom correspondence should be addressed. E-mail: b.holst{at}molpharm.dk;.

Two non-peptide (L692,429 and MK-677) and two peptide (GHRP-6 and ghrelin) agonists were compared in binding and in signal transduction assays: calcium mobilization, inositol phosphate turnover, cAMP responsive element (CRE) and serum responsive element (SRE) controlled transcription, as well as arrestin mobilization. MK-677 acted as a simple agonist having an affinity of 6.5 nM and activated all signal transduction systems with similar high potency (0.2-1.4 nM). L-692,429 also displayed a very similar potency in all signaling assays (25-60 nM) but competed with a 1000-fold lower apparent affinity for ghrelin binding and surprisingly acted as a positive allosteric receptor modulator by increasing ghrelin's potency 4-10 fold. In contrast, the potency of GHRP-6 varied 600-fold (0.1-61 nM) depending on the signal transduction assay and it acted as a negative allosteric modulator of ghrelin signaling. Unexpectedly, the maximal signaling efficacy for ghrelin was increased above what was observed with the hormone itself during co-administration with the non-endogenous agonists. It is concluded that agonists for the ghrelin receptor vary both in respect of their intrinsic agonist properties and in their ability to modulate ghrelin signaling. A receptor model is presented wherein ghrelin normally only activates one receptor subunit in a dimer and where the smaller non-endogenous agonists bind in the other subunit to act both as co-agonists and as either neutral (MK-677), positive (L-692,429), or negative (GHRP- 6) modulators of ghrelin function. It is suggested that an optimal drug candidate could be an agonist which also is a positive modulator of ghrelin signaling.




This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
P. C. Jensen, S. Thiele, T. Ulven, T. W. Schwartz, and M. M. Rosenkilde
Positive Versus Negative Modulation of Different Endogenous Chemokines for CC-chemokine Receptor 1 by Small Molecule Agonists through Allosteric Versus Orthosteric Binding
J. Biol. Chem., August 22, 2008; 283(34): 23121 - 23128.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
J.-N. Ma, H. H. Schiffer, A. E. Knapp, J. Wang, K. K. Wong, E. A. Currier, M. Owens, N. R. Nash, L. R. Gardell, M. R. Brann, et al.
Identification of the Atypical L-Type Ca2+ Channel Blocker Diltiazem and Its Metabolites As Ghrelin Receptor Agonists
Mol. Pharmacol., August 1, 2007; 72(2): 380 - 386.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. Holst, J. Mokrosinski, M. Lang, E. Brandt, R. Nygaard, T. M. Frimurer, A. G. Beck-Sickinger, and T. W. Schwartz
Identification of an Efficacy Switch Region in the Ghrelin Receptor Responsible for Interchange between Agonism and Inverse Agonism
J. Biol. Chem., May 25, 2007; 282(21): 15799 - 15811.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
B. Holst, M. Lang, E. Brandt, A. Bach, A. Howard, T. M. Frimurer, A. Beck-Sickinger, and T. W. Schwartz
Ghrelin Receptor Inverse Agonists: Identification of an Active Peptide Core and Its Interaction Epitopes on the Receptor
Mol. Pharmacol., September 1, 2006; 70(3): 936 - 946.
[Abstract] [Full Text] [PDF]

Home page
 J Mol EndocrinolHome page
R M Luque, J R Peinado, F Gracia-Navarro, F Broglio, E Ghigo, R D Kineman, M M Malagon, and J P Castano
Cortistatin mimics somatostatin by inducing a dual, dose-dependent stimulatory and inhibitory effect on growth hormone secretion in somatotropes.
J. Mol. Endocrinol., June 1, 2006; 36(3): 547 - 556.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2005 by The Endocrine Society