HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 26, 23731-23737, June 27, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/26/23731    most recent M212369200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hilairet, S. Articles by Casellas, P. Search for Related Content PubMed PubMed Citation Articles by Hilairet, S. Articles by Casellas, P. Social Bookmarking                      What's this?

Hypersensitization of the Orexin 1 Receptor by the CB1 Receptor

EVIDENCE FOR CROSS-TALK BLOCKED BY THE SPECIFIC CB1 ANTAGONIST, SR141716^*

Sandrine Hilairet  , Monsif Bouaboula  , Dominique Carrière , Gérard Le Fur ¶ and Pierre Casellas  ||

From the Immunology-Oncology Department, Sanofi-Synthelabo Recherche, 371 rue du Professeur J. Blayac, 34184 Montpellier, CEDEX 04, France and the ^¶Sanofi-Synthelabo recherche, 174, Avenue de France, 75635 Paris, CEDEX 13, France

In the present study, we observed evidence of cross-talk between the cannabinoid receptor CB1 and the orexin 1 receptor (OX1R) using a heterologous system. When the two receptors are co-expressed, we observed a major CB1-dependent enhancement of the orexin A potency to activate the mitogen-activated protein kinase pathway; dose-responses curves indicated a 100-fold increase in the potency of orexin-mediated mitogen-activated protein kinase activation. This effect required a functional CB1 receptor as evidenced by the blockade of the orexin response by the specific CB1 antagonist, N-(piperidino-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide (SR141716), but also by pertussis toxin, suggesting that this potentiation is G_i-mediated. In contrast to OX1R, the potency of direct activation of CB1 was not affected by co-expression with OX1R. In addition, electron microscopy experiments revealed that CB1 and OX1R are closely apposed at the plasma membrane level; they are close enough to form hetero-oligomers. Altogether, for the first time our data provide evidence that CB1 is able to potentiate an orexigenic receptor. Considering the antiobesity effect of SR141716, these results open new avenues to understand the mechanism by which the molecule may prevent weight gain through functional interaction between CB1 and other receptors involved in the control of appetite.

Received for publication, December 4, 2002 , and in revised form, March 20, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^|| To whom correspondence should be addressed. Tel.: 33-4-67-10-62-90; Fax: 33-4-67-10-60-00; E-mail: pierre.casellas{at}sanofi-synthelabo.com.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. Guan, X. Feng, X. Wu, M. Zhang, X. Zhang, T. E. Hebert, and D. L. Segaloff Bioluminescence Resonance Energy Transfer Studies Reveal Constitutive Dimerization of the Human Lutropin Receptor and a Lack of Correlation between Receptor Activation and the Propensity for Dimerization J. Biol. Chem., March 20, 2009; 284(12): 7483 - 7494. [Abstract] [Full Text] [PDF]

				M. Kano, T. Ohno-Shosaku, Y. Hashimotodani, M. Uchigashima, and M. Watanabe Endocannabinoid-Mediated Control of Synaptic Transmission Physiol Rev, January 1, 2009; 89(1): 309 - 380. [Abstract] [Full Text] [PDF]

				M. Ramanjaneya, A. C. Conner, J. Chen, P. R. Stanfield, and H. S. Randeva Orexins Stimulate Steroidogenic Acute Regulatory Protein Expression through Multiple Signaling Pathways in Human Adrenal H295R Cells Endocrinology, August 1, 2008; 149(8): 4106 - 4115. [Abstract] [Full Text] [PDF]

				M. Canals and G. Milligan Constitutive Activity of the Cannabinoid CB1 Receptor Regulates the Function of Co-expressed Mu Opioid Receptors J. Biol. Chem., April 25, 2008; 283(17): 11424 - 11434. [Abstract] [Full Text] [PDF]

				M. Bifulco, C. Grimaldi, P. Gazzerro, S. Pisanti, and A. Santoro Rimonabant: Just an Antiobesity Drug? Current Evidence on Its Pleiotropic Effects Mol. Pharmacol., June 1, 2007; 71(6): 1445 - 1456. [Abstract] [Full Text] [PDF]

				J. Ellis, J. D. Pediani, M. Canals, S. Milasta, and G. Milligan Orexin-1 Receptor-Cannabinoid CB1 Receptor Heterodimerization Results in Both Ligand-dependent and -independent Coordinated Alterations of Receptor Localization and Function J. Biol. Chem., December 15, 2006; 281(50): 38812 - 38824. [Abstract] [Full Text] [PDF]

				P. Pacher, S. Batkai, and G. Kunos The Endocannabinoid System as an Emerging Target of Pharmacotherapy Pharmacol. Rev., September 1, 2006; 58(3): 389 - 462. [Abstract] [Full Text] [PDF]

				U. Pagotto, G. Marsicano, D. Cota, B. Lutz, and R. Pasquali The Emerging Role of the Endocannabinoid System in Endocrine Regulation and Energy Balance Endocr. Rev., February 1, 2006; 27(1): 73 - 100. [Abstract] [Full Text] [PDF]

				S. Ammoun, D. Lindholm, H. Wootz, K. E. O. Akerman, and J. P. Kukkonen G-protein-coupled OX1 Orexin/hcrtr-1 Hypocretin Receptors Induce Caspase-dependent and -independent Cell Death through p38 Mitogen-/Stress-activated Protein Kinase J. Biol. Chem., January 13, 2006; 281(2): 834 - 842. [Abstract] [Full Text] [PDF]

				S. Ammoun, L. Johansson, M. E. Ekholm, T. Holmqvist, A. S. Danis, L. Korhonen, O. A. Sergeeva, H. L. Haas, K. E. O. Akerman, and J. P. Kukkonen OX1 Orexin Receptors Activate Extracellular Signal-Regulated Kinase in Chinese Hamster Ovary Cells via Multiple Mechanisms: The Role of Ca2+ Influx in OX1 Receptor Signaling Mol. Endocrinol., January 1, 2006; 20(1): 80 - 99. [Abstract] [Full Text] [PDF]

				C. S. Kearn, K. Blake-Palmer, E. Daniel, K. Mackie, and M. Glass Concurrent Stimulation of Cannabinoid CB1 and Dopamine D2 Receptors Enhances Heterodimer Formation: A Mechanism for Receptor Cross-Talk? Mol. Pharmacol., May 1, 2005; 67(5): 1697 - 1704. [Abstract] [Full Text] [PDF]

				E. Fride, T. Bregman, and T. C. Kirkham Endocannabinoids and Food Intake: Newborn Suckling and Appetite Regulation in Adulthood Experimental Biology and Medicine, April 1, 2005; 230(4): 225 - 234. [Abstract] [Full Text] [PDF]

				M. Hirasawa, Y. Schwab, S. Natah, C. J. Hillard, K. Mackie, K. A. Sharkey, and Q. J. Pittman Dendritically released transmitters cooperate via autocrine and retrograde actions to inhibit afferent excitation in rat brain J. Physiol., September 1, 2004; 559(2): 611 - 624. [Abstract] [Full Text] [PDF]

				P. Casellas CB2, a paradigm for a novel class of "onco-GPCRs"? Blood, July 15, 2004; 104(2): 302 - 303. [Full Text] [PDF]

				G. Burdyga, S. Lal, A. Varro, R. Dimaline, D. G. Thompson, and G. J. Dockray Expression of Cannabinoid CB1 Receptors by Vagal Afferent Neurons Is Inhibited by Cholecystokinin J. Neurosci., March 17, 2004; 24(11): 2708 - 2715. [Abstract] [Full Text] [PDF]

				R. A. Bakker, P. Casarosa, H. Timmerman, M. J. Smit, and R. Leurs Constitutively active Gq/11-coupled Receptors Enable Signaling by Co-expressed Gi/o-coupled Receptors J. Biol. Chem., February 13, 2004; 279(7): 5152 - 5161. [Abstract] [Full Text] [PDF]