Advertisement
JBC

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published In Press as doi:10.1074/jbc.M202103200 on September 18, 2002

J. Biol. Chem., Vol. 277, Issue 49, 47662-47670, December 6, 2002
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
277/49/47662    most recent
M202103200v1
Right arrow Submit a Letter to Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
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 arrowRequest Permissions
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.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Metal Ion-mediated Agonism and Agonist Enhancement in Melanocortin MC1 and MC4 Receptors*

Birgitte HolstDagger §, Christian E. Elling§, and Thue W. SchwartzDagger §

From the Dagger  Laboratory for Molecular Pharmacology, Institute of Pharmacology, University of Copenhagen, The Panum Institute, Blegdamsvej 3, Copenhagen DK-2200 and § 7TM Pharma A/S, Rønnegade 2, Copenhagen, DK-2100, Denmark

An endogenous metal-ion site in the melanocortin MC1 and MC4 receptors was characterized mainly in transiently transfected COS-7 cells. ZnCl2 alone stimulated signaling through the Gs pathway with a potency of 11 and 13 µM and an efficacy of 50 and 20% of that of alpha -melanocortin stimulating hormone (alpha -MSH) in the MC1 and MC4 receptors, respectively. In the presence of peptide agonist, Zn(II) acted as an enhancer on both receptors, because it shifted the dose-response curves to the left: most pronounced was a 6-fold increase in alpha -MSH potency on the MC1 receptor. The effect of the metal ion appeared to be additive, because the maximal cAMP response for alpha -MSH in the presence of Zn(II) was 60% above the maximal response for the peptide alone. The affinity of Zn(II) could be increased through binding of the metal ion in complex with small hydrophobic chelators. The binding affinities and profiles were similar for a number of the 2,2'-bipyridine and 1,10-phenanthroline analogs in complex with Zn(II) in the MC1 and MC4 receptors. However, the potencies and efficacies of the metal-ion complexes were very different in the two receptors, and close to full agonism was obtained in the MC1 receptor. Metal ion-chelator complexes having antagonistic properties were also found. An initial attempt to map the metal-ion binding site in the MC1 receptor indicated that Cys271 in extracellular loop 3 and possibly Asp119 at the extracellular end of TM-III, which are both conserved among all MC receptors, are parts of the site. It is concluded that the function of the MC1 and MC4 receptors can be positively modulated by metal ions acting both as partial agonists and as potentiators for other agonists, including the endogenous peptide ligand alpha -MSH at Zn(II) concentrations that could be physiological. Furthermore, the metal ion-chelator complexes may serve as leads in the development of novel melanocortin receptor modulators.

* This study was supported in part by grants from The Novo Nordisk Foundation and the Danish Medical and Science Research Council.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a postdoctoral stipend from the Danish Medical Research Council. To whom correspondence should be addressed. Tel.: 45-3532-7606; Fax: 45-3532-7610; E-mail: b.holst@molpharm.dk.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 EndocrinologyHome page
F. Tremblay, A.-M. T. Richard, S. Will, J. Syed, N. Stedman, M. Perreault, and R. E. Gimeno
Disruption of G Protein-Coupled Receptor 39 Impairs Insulin Secretion in Vivo
Endocrinology, June 1, 2009; 150(6): 2586 - 2595.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
B. Holst, T. M. Frimurer, J. Mokrosinski, T. Halkjaer, K. B. Cullberg, C. R. Underwood, and T. W. Schwartz
Overlapping Binding Site for the Endogenous Agonist, Small-Molecule Agonists, and Ago-allosteric Modulators on the Ghrelin Receptor
Mol. Pharmacol., January 1, 2009; 75(1): 44 - 59.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
F. F. Casanueva, J. P. Camina, M. C. Carreira, Y. Pazos, J. L. Varga, and A. V. Schally
Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a
PNAS, December 23, 2008; 105(51): 20452 - 20457.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
P. S.-H. Park, K. T. Sapra, M. Kolinski, S. Filipek, K. Palczewski, and D. J. Muller
Stabilizing Effect of Zn2+ in Native Bovine Rhodopsin
J. Biol. Chem., April 13, 2007; 282(15): 11377 - 11385.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
L. B. Knudsen, D. Kiel, M. Teng, C. Behrens, D. Bhumralkar, J. T. Kodra, J. J. Holst, C. B. Jeppesen, M. D. Johnson, J. C. de Jong, et al.
From the Cover: Small-molecule agonists for the glucagon-like peptide 1 receptor
PNAS, January 16, 2007; 104(3): 937 - 942.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
B. Holst, K. L. Egerod, E. Schild, S. P. Vickers, S. Cheetham, L.-O. Gerlach, L. Storjohann, C. E. Stidsen, R. Jones, A. G. Beck-Sickinger, et al.
GPR39 Signaling Is Stimulated by Zinc Ions But Not by Obestatin
Endocrinology, January 1, 2007; 148(1): 13 - 20.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. E. Elling, T. M. Frimurer, L.-O. Gerlach, R. Jorgensen, B. Holst, and T. W. Schwartz
Metal Ion Site Engineering Indicates a Global Toggle Switch Model for Seven-transmembrane Receptor Activation
J. Biol. Chem., June 23, 2006; 281(25): 17337 - 17346.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
B. Holst, E. Brandt, A. Bach, A. Heding, and T. W. Schwartz
Nonpeptide and Peptide Growth Hormone Secretagogues Act Both as Ghrelin Receptor Agonist and as Positive or Negative Allosteric Modulators of Ghrelin Signaling
Mol. Endocrinol., September 1, 2005; 19(9): 2400 - 2411.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
A. Slominski, P. M. Plonka, A. Pisarchik, J. L. Smart, V. Tolle, J. Wortsman, and M. J. Low
Preservation of Eumelanin Hair Pigmentation in Proopiomelanocortin-Deficient Mice on a Nonagouti (a/a) Genetic Background
Endocrinology, March 1, 2005; 146(3): 1245 - 1253.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. Stojanovic, J. Stitham, and J. Hwa
Critical Role of Transmembrane Segment Zinc Binding in the Structure and Function of Rhodopsin
J. Biol. Chem., August 20, 2004; 279(34): 35932 - 35941.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. C. Lagerstrom, J. Klovins, R. Fredriksson, D. Fridmanis, T. Haitina, M. K. Ling, M. M. Berglund, and H. B. Schioth
High Affinity Agonistic Metal Ion Binding Sites within the Melanocortin 4 Receptor Illustrate Conformational Change of Transmembrane Region 3
J. Biol. Chem., December 19, 2003; 278(51): 51521 - 51526.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
P. Tarnow, T. Schoneberg, H. Krude, A. Gruters, and H. Biebermann
Mutationally Induced Disulfide Bond Formation within the Third Extracellular Loop Causes Melanocortin 4 Receptor Inactivation in Patients with Obesity
J. Biol. Chem., December 5, 2003; 278(49): 48666 - 48673.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.
Advertisement
spacer
Advertisement
Advertisement