help button home button Endocrine Society Molecular Endocrinology ENDO 08 Sessions Library
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
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 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 Nijenhuis, W. A. J.
Right arrow Articles by Adan, R. A. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nijenhuis, W. A. J.
Right arrow Articles by Adan, R. A. H.
Molecular Endocrinology 15 (1): 164-171
Copyright © 2001 by The Endocrine Society

AgRP(83–132) Acts as an Inverse Agonist on the Human-Melanocortin-4 Receptor

Wouter A. J. Nijenhuis, Julia Oosterom and Roger A. H. Adan

Molecular Neuroscience Rudolf Magnus Institute for Neurosciences University Medical Center Utrecht Utrecht, the Netherlands 3584 CG

The central melanocortin (MC) system has been demonstrated to act downstream of leptin in the regulation of body weight. The system comprises {alpha}-MSH, which acts as agonist, and agouti-related protein (AgRP), which acts as antagonist at the MC3 and MC4 receptors (MC3R and MC4R). This property suggests that MCR activity is tightly regulated and that opposing signals are integrated at the receptor level. We here propose another level of regulation within the melanocortin system by showing that the human (h) MC4R displays constitutive activity in vitro as assayed by adenylyl cyclase (AC) activity. Furthermore, human AgRP(83–132) acts as an inverse agonist for the hMC4R since it was able to suppress constitutive activity of the hMC4R both in intact B16/G4F melanoma cells and membrane preparations. The effect of AgRP(83–132) on the hMC4R was blocked by the MC4R ligand SHU9119. Also the hMC3R and the mouse(m)MC5R were shown to be constitutively active. AgRP(83–132) acted as an inverse agonist on the hMC3R but not on the mMC5R. Thus, AgRP is able to regulate MCR activity independently of {alpha}-MSH. These findings form a basis to further investigate the relevance of constitutive activity of the MC4R and of inverse agonism of AgRP for the regulation of body weight.




This article has been cited by other articles:


Home page
 EndocrinologyHome page
P. S. Petersen, D. P. D. Woldbye, A. N. Madsen, K. L. Egerod, C. Jin, M. Lang, M. Rasmussen, A. G. Beck-Sickinger, and B. Holst
In Vivo Characterization of High Basal Signaling from the Ghrelin Receptor
Endocrinology, November 1, 2009; 150(11): 4920 - 4930.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
T. R. H. Buch, D. Heling, E. Damm, T. Gudermann, and A. Breit
Pertussis Toxin-sensitive Signaling of Melanocortin-4 Receptors in Hypothalamic GT1-7 Cells Defines Agouti-related Protein as a Biased Agonist
J. Biol. Chem., September 25, 2009; 284(39): 26411 - 26420.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
E. Sanchez, V. C. Rubio, D. Thompson, J. Metz, G. Flik, G. L. Millhauser, and J. M. Cerda-Reverter
Phosphodiesterase inhibitor-dependent inverse agonism of agouti-related protein on melanocortin 4 receptor in sea bass (Dicentrarchus labrax)
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2009; 296(5): R1293 - R1306.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
W. Pan, H. Hsuchou, Y. He, A. Sakharkar, C. Cain, C. Yu, and A. J. Kastin
Astrocyte Leptin Receptor (ObR) and Leptin Transport in Adult-Onset Obese Mice
Endocrinology, June 1, 2008; 149(6): 2798 - 2806.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
L.-Y. Fu and A. N. van den Pol
Agouti-Related Peptide and MC3/4 Receptor Agonists Both Inhibit Excitatory Hypothalamic Ventromedial Nucleus Neurons
J. Neurosci., May 21, 2008; 28(21): 5433 - 5449.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
K. Janssens, M. Boussemaere, S. Wagner, K. Kopka, and C. Denef
{beta}1-Adrenoceptors in Rat Anterior Pituitary May Be Constitutively Active. Inverse Agonism of CGP 20712A on Basal 3',5'-Cyclic Adenosine 5'-Monophosphate Levels
Endocrinology, May 1, 2008; 149(5): 2391 - 2402.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
V. Tolle and M. J. Low
In Vivo Evidence for Inverse Agonism of Agouti-Related Peptide in the Central Nervous System of Proopiomelanocortin-Deficient Mice
Diabetes, January 1, 2008; 57(1): 86 - 94.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
H. Shimizu, K. Inoue, and M. Mori
The leptin-dependent and -independent melanocortin signaling system: regulation of feeding and energy expenditure
J. Endocrinol., April 1, 2007; 193(1): 1 - 9.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Mohammad, G. Baldini, S. Granell, P. Narducci, A. M. Martelli, and G. Baldini
Constitutive Traffic of Melanocortin-4 Receptor in Neuro2A Cells and Immortalized Hypothalamic Neurons
J. Biol. Chem., February 16, 2007; 282(7): 4963 - 4974.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
M. A. Smith, K. Hisadome, H. Al-Qassab, H. Heffron, D. J. Withers, and M. L. J. Ashford
Melanocortins and agouti-related protein modulate the excitability of two arcuate nucleus neuron populations by alteration of resting potassium conductances
J. Physiol., January 15, 2007; 578(2): 425 - 438.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. Breit, K. Wolff, H. Kalwa, H. Jarry, T. Buch, and T. Gudermann
The Natural Inverse Agonist Agouti-related Protein Induces Arrestin-mediated Endocytosis of Melanocortin-3 and -4 Receptors
J. Biol. Chem., December 8, 2006; 281(49): 37447 - 37456.
[Abstract] [Full Text] [PDF]

Home page
 J Mol EndocrinolHome page
H D. Falls, B. D Dayton, D. G Fry, C. A Ogiela, V. G Schaefer, S. Brodjian, R. M Reilly, C. A Collins, and W. Kaszubska
Characterization of ghrelin receptor activity in a rat pituitary cell line RC-4B/C.
J. Mol. Endocrinol., August 1, 2006; 37(1): 51 - 62.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
M. Perello, R. C. Stuart, and E. A. Nillni
The Role of Intracerebroventricular Administration of Leptin in the Stimulation of Prothyrotropin Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus
Endocrinology, July 1, 2006; 147(7): 3296 - 3306.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
S. Aja, S. Bi, S. B. Knipp, J. M. McFadden, G. V. Ronnett, F. P. Kuhajda, and T. H. Moran
Intracerebroventricular C75 decreases meal frequency and reduces AgRP gene expression in rats
Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2006; 291(1): R148 - R154.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. M. Rosenkilde, T. Benned-Jensen, H. Andersen, P. J. Holst, T. N. Kledal, H. R. Luttichau, J. K. Larsen, J. P. Christensen, and T. W. Schwartz
Molecular Pharmacological Phenotyping of EBI2: AN ORPHAN SEVEN-TRANSMEMBRANE RECEPTOR WITH CONSTITUTIVE ACTIVITY
J. Biol. Chem., May 12, 2006; 281(19): 13199 - 13208.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
J. R. Nicholson, G. Kohler, F. Schaerer, C. Senn, P. Weyermann, and K. G. Hofbauer
Peripheral Administration of a Melanocortin 4-Receptor Inverse Agonist Prevents Loss of Lean Body Mass in Tumor-Bearing Mice
J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 771 - 777.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
C. Lubrano-Berthelier, B. Dubern, J.-M. Lacorte, F. Picard, A. Shapiro, S. Zhang, S. Bertrais, S. Hercberg, A. Basdevant, K. Clement, et al.
Melanocortin 4 Receptor Mutations in a Large Cohort of Severely Obese Adults: Prevalence, Functional Classification, Genotype-Phenotype Relationship, and Lack of Association with Binge Eating
J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1811 - 1818.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. W. M. Creemers, L. E. Pritchard, A. Gyte, P. Le Rouzic, S. Meulemans, S. L. Wardlaw, X. Zhu, D. F. Steiner, N. Davies, D. Armstrong, et al.
Agouti-Related Protein Is Posttranslationally Cleaved by Proprotein Convertase 1 to Generate Agouti-Related Protein (AGRP)83-132: Interaction between AGRP83-132 and Melanocortin Receptors Cannot Be Influenced by Syndecan-3
Endocrinology, April 1, 2006; 147(4): 1621 - 1631.
[Abstract] [Full Text] [PDF]

Home page
 JCBHome page
L. Freudzon, R. P. Norris, A. R. Hand, S. Tanaka, Y. Saeki, T. L.Z. Jones, M. M. Rasenick, C. H. Berlot, L. M. Mehlmann, and L. A. Jaffe
Regulation of meiotic prophase arrest in mouse oocytes by GPR3, a constitutive activator of the Gs G protein
J. Cell Biol., October 24, 2005; 171(2): 255 - 265.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
G. M. Sutton, B. Duos, L. M. Patterson, and H.-R. Berthoud
Melanocortinergic Modulation of Cholecystokinin-Induced Suppression of Feeding through Extracellular Signal-Regulated Kinase Signaling in Rat Solitary Nucleus
Endocrinology, September 1, 2005; 146(9): 3739 - 3747.
[Abstract] [Full Text] [PDF]

Home page
 J Mol EndocrinolHome page
M. J H Kas, A. W Bruijnzeel, J. R Haanstra, V. M Wiegant, and R. A H Adan
Differential regulation of agouti-related protein and neuropeptide Y in hypothalamic neurons following a stressful event
J. Mol. Endocrinol., August 1, 2005; 35(1): 159 - 164.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
S. Markison, A. C. Foster, C. Chen, G. B. Brookhart, A. Hesse, S. R. J. Hoare, B. A. Fleck, B. T. Brown, and D. L. Marks
The Regulation of Feeding and Metabolic Rate and the Prevention of Murine Cancer Cachexia with a Small-Molecule Melanocortin-4 Receptor Antagonist
Endocrinology, June 1, 2005; 146(6): 2766 - 2773.
[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
 HypertensionHome page
L. S. Tallam, J. J. Kuo, A. A. da Silva, and J. E. Hall
Cardiovascular, Renal, and Metabolic Responses to Chronic Central Administration of Agouti-Related Peptide
Hypertension, December 1, 2004; 44(6): 853 - 858.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
C. Fekete, D. L. Marks, S. Sarkar, C. H. Emerson, W. M. Rand, R. D. Cone, and R. M. Lechan
Effect of Agouti-Related Protein in Regulation of the Hypothalamic-Pituitary-Thyroid Axis in the Melanocortin 4 Receptor Knockout Mouse
Endocrinology, November 1, 2004; 145(11): 4816 - 4821.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. Leterrier, D. Bonnard, D. Carrel, J. Rossier, and Z. Lenkei
Constitutive Endocytic Cycle of the CB1 Cannabinoid Receptor
J. Biol. Chem., August 20, 2004; 279(34): 36013 - 36021.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
E. Savontaus, T. L. Breen, A. Kim, L. M. Yang, S. C. Chua Jr., and S. L. Wardlaw
Metabolic Effects of Transgenic Melanocyte-Stimulating Hormone Overexpression in Lean and Obese Mice
Endocrinology, August 1, 2004; 145(8): 3881 - 3891.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
L. Huo, H. Munzberg, E. A. Nillni, and C. Bjorbaek
Role of Signal Transducer and Activator of Transcription 3 in Regulation of Hypothalamic trh Gene Expression by Leptin
Endocrinology, May 1, 2004; 145(5): 2516 - 2523.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
T. Zimmermann-Belsing and U. Feldt-Rasmussen
Obesity: The New Worldwide Epidemic Threat to General Health and Our Complete Lack of Effective Treatment
Endocrinology, April 1, 2004; 145(4): 1501 - 1502.
[Full Text] [PDF]

Home page
 J BiochemHome page
A. Blondet, M. Doghman, M. Rached, P. Durand, M. Begeot, and D. Naville
Characterization of Cell Lines Stably Expressing Human Normal or Mutated EGFP-Tagged MC4R
J. Biochem., April 1, 2004; 135(4): 541 - 546.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
T. Kenakin
Efficacy as a Vector: the Relative Prevalence and Paucity of Inverse Agonism
Mol. Pharmacol., January 1, 2004; 65(1): 2 - 11.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
G. Milligan
Constitutive Activity and Inverse Agonists of G Protein-Coupled Receptors: a Current Perspective
Mol. Pharmacol., December 1, 2003; 64(6): 1271 - 1276.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
B. Holst, A. Cygankiewicz, T. H. Jensen, M. Ankersen, and T. W. Schwartz
High Constitutive Signaling of the Ghrelin Receptor--Identification of a Potent Inverse Agonist
Mol. Endocrinol., November 1, 2003; 17(11): 2201 - 2210.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
Y. Yang, M. Chen, Y. Lai, I. Gantz, A. Yagmurlu, K. E. Georgeson, and C. M. Harmon
Molecular Determination of Agouti-Related Protein Binding to Human Melanocortin-4 Receptor
Mol. Pharmacol., July 1, 2003; 64(1): 94 - 103.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
W. A. J. Nijenhuis, K. M. Garner, R. J. van Rozen, and R. A. H. Adan
Poor Cell Surface Expression of Human Melanocortin-4 Receptor Mutations Associated with Obesity
J. Biol. Chem., June 13, 2003; 278(25): 22939 - 22945.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D. VanLeeuwen, M. E. Steffey, C. Donahue, G. Ho, and R. G. MacKenzie
Cell Surface Expression of the Melanocortin-4 Receptor Is Dependent on a C-terminal Di-isoleucine Sequence at Codons 316/317
J. Biol. Chem., April 25, 2003; 278(18): 15935 - 15940.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
H. Shinyama, H. Masuzaki, H. Fang, and J. S. Flier
Regulation of Melanocortin-4 Receptor Signaling: Agonist-Mediated Desensitization and Internalization
Endocrinology, April 1, 2003; 144(4): 1301 - 1314.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
I. Gantz and T. M. Fong
The melanocortin system
Am J Physiol Endocrinol Metab, March 1, 2003; 284(3): E468 - E474.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
S. A. Nickolls, M. I. Cismowski, X. Wang, M. Wolff, P. J. Conlon, and R. A. Maki
Molecular Determinants of Melanocortin 4 Receptor Ligand Binding and MC4/MC3 Receptor Selectivity
J. Pharmacol. Exp. Ther., March 1, 2003; 304(3): 1217 - 1227.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
C. Lubrano-Berthelier, E. Durand, B. Dubern, A. Shapiro, P. Dazin, J. Weill, C. Ferron, P. Froguel, and C. Vaisse
Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations
Hum. Mol. Genet., January 15, 2003; 12(2): 145 - 153.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
S. Sarkar and R. M. Lechan
Central Administration of Neuropeptide Y Reduces {alpha}-Melanocyte-Stimulating Hormone-Induced Cyclic Adenosine 5'-Monophosphate Response Element Binding Protein (CREB) Phosphorylation in Pro-Thyrotropin-Releasing Hormone Neurons and Increases CREB Phosphorylation in Corticotropin-Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus
Endocrinology, January 1, 2003; 144(1): 281 - 291.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
C. Fekete, S. Sarkar, W. M. Rand, J. W. Harney, C. H. Emerson, A. C. Bianco, and R. M. Lechan
Agouti-Related Protein (AGRP) Has a Central Inhibitory Action on the Hypothalamic-Pituitary-Thyroid (HPT) Axis; Comparisons between the Effect of AGRP and Neuropeptide Y on Energy Homeostasis and the HPT Axis
Endocrinology, October 1, 2002; 143(10): 3846 - 3853.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. S. Kim, S.-H. Lee, R. Y. Kim, B.-J. Kim, S.-Z. Li, I. H. Lee, E. J. Lee, S.-K. Lim, Y.-S. Bae, W. Lee, et al.
Identification of Domains Directing Specificity of Coupling to G-proteins for the Melanocortin MC3 and MC4 Receptors
J. Biol. Chem., August 23, 2002; 277(35): 31310 - 31317.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
Y.-K. Yang, C. Dickinson, Y.-M. Lai, J.-Y. Li, and I. Gantz
Functional properties of an agouti signaling protein variant and characteristics of its cognate radioligand
Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2001; 281(6): R1877 - R1886.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
R. M. Lechan and J. B. Tatro
Editorial: Hypothalamic Melanocortin Signaling in Cachexia
Endocrinology, August 1, 2001; 142(8): 3288 - 3291.
[Full Text] [PDF]

Home page
 EndocrinologyHome page
B. E. Wisse, R. S. Frayo, M. W. Schwartz, and D. E. Cummings
Reversal of Cancer Anorexia by Blockade of Central Melanocortin Receptors in Rats
Endocrinology, August 1, 2001; 142(8): 3292 - 3301.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
Y. Kiriyama, H. Tsuchiya, T. Murakami, K. Satoh, and Y. Tokumitsu
Calcitonin Induces IL-6 Production via Both PKA and PKC Pathways in the Pituitary Folliculo-Stellate Cell Line
Endocrinology, August 1, 2001; 142(8): 3563 - 3569.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2001 by The Endocrine Society