Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

PNAS 102 (25): 9050-9055

Copyright © 2005 by the National Academy of Sciences.

From the Cover

PHARMACOLOGY

A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers

Maria Waldhoer *, Jamie Fong *, Robert M. Jones {dagger}, Mary M. Lunzer {ddagger}, Shiv K. Sharma {ddagger}, Evi Kostenis §, Philip S. Portoghese {ddagger}, ¶, and Jennifer L. Whistler *, ||

*Ernest Gallo Clinic and Research Center, University of California, San Francisco, CA 94608; {ddagger}Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455; {dagger}Department of Medicinal Chemistry, Arena Pharmaceuticals, San Diego, CA 92121; and §7TM Pharma, 2970 Hørsholm, Denmark

Edited by Richard P. Lifton, Yale University School of Medicine, New Haven, CT, and approved April 28, 2005

Received for publication February 9, 2005.

Abstract: There has been much speculation regarding the functional relevance of G protein-coupled receptor heterodimers, primarily because demonstrating their existence in vivo has proven to be a considerable challenge. Here we show that the opioid agonist ligand 6'-guanidinonaltrindole (6'-GNTI) has the unique property of selectively activating only opioid receptor heterodimers but not homomers. Importantly, 6'-GNTI is an analgesic, thereby demonstrating that opioid receptor heterodimers are indeed functionally relevant in vivo. However, 6'-GNTI induces analgesia only when it is administered in the spinal cord but not in the brain, suggesting that the organization of heterodimers is tissue-specific. This study demonstrates a proof of concept for tissue-selective drug targeting based on G protein-coupled receptor heterodimerization. Importantly, targeting opioid heterodimers could provide an approach toward the design of analgesic drugs with reduced side effects.

Key Words: opioid

Author contributions: M.W., P.S.P., and J.L.W. designed research; M.W., J.F., and M.M.L. performed research; M.W., R.M.J., S.K.S., E.K., and P.S.P. contributed new reagents/analytic tools; M.W., M.M.L., P.S.P., and J.L.W. analyzed data; M.W., P.S.P., and J.L.W. wrote the paper; and E.K. edited the manuscript.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: GPCR, G protein-coupled receptor; DOP, delta opioid peptide; DOP-R, DOP receptor; KOP, kappa opioid peptide; KOP-R, KOP receptor; MOP, mu opioid peptide; MOP-R, MOP receptor; 6'-GNTI, 6'-guanidinonaltrindole; i.t., intrathecally; HA, hemagglutinin; NTI, naltrindole; NorBNI, nor-binaltorphimine.

See Commentary on page 8793.

To whom correspondence may be addressed at: Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN 55455. E-mail: porto001{at}umn.edu. ||To whom correspondence may be addressed at: Ernest Gallo Research Center, University of California at San Francisco, 5858 Horton Street, Suite 200, Emeryville, CA 94608. E-mail: shooz2{at}itsa.ucsf.edu.

© 2005 by The National Academy of Sciences of the USA

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The Cannabinoid Receptor CB1 Modulates the Signaling Properties of the Lysophosphatidylinositol Receptor GPR55.
J. Kargl, N. Balenga, G. P. Parzmair, A. J. Brown, A. Heinemann, and M. Waldhoer (2012)
J. Biol. Chem. 287, 44234-44248
   Abstract »    Full Text »    PDF »
Computational and Experimental Analysis of the Transmembrane Domain 4/5 Dimerization Interface of the Serotonin 5-HT1A Receptor.
N. Gorinski, N. Kowalsman, U. Renner, A. Wirth, M. T. Reinartz, R. Seifert, A. Zeug, E. Ponimaskin, and M. Y. Niv (2012)
Mol. Pharmacol. 82, 448-463
   Abstract »    Full Text »    PDF »
6'-Guanidinonaltrindole (6'-GNTI) Is a G Protein-biased {kappa}-Opioid Receptor Agonist That Inhibits Arrestin Recruitment.
M.-L. Rives, M. Rossillo, L.-Y. Liu-Chen, and J. A. Javitch (2012)
J. Biol. Chem. 287, 27050-27054
   Abstract »    Full Text »    PDF »
Heterodimerization of serotonin receptors 5-HT1A and 5-HT7 differentially regulates receptor signalling and trafficking.
U. Renner, A. Zeug, A. Woehler, M. Niebert, A. Dityatev, G. Dityateva, N. Gorinski, D. Guseva, D. Abdel-Galil, M. Frohlich, et al. (2012)
J. Cell Sci. 125, 2486-2499
   Abstract »    Full Text »    PDF »
Cys-27 Variant of Human {delta}-Opioid Receptor Modulates Maturation and Cell Surface Delivery of Phe-27 Variant via Heteromerization.
T. T. Leskela, J. J. Lackman, M. M. Vierimaa, H. Kobayashi, M. Bouvier, and U. E. Petaja-Repo (2012)
J. Biol. Chem. 287, 5008-5020
   Abstract »    Full Text »    PDF »
Allosteric Interactions between {delta} and {kappa} Opioid Receptors in Peripheral Sensory Neurons.
K. A. Berg, M. P. Rowan, A. Gupta, T. A. Sanchez, M. Silva, I. Gomes, B. A. McGuire, P. S. Portoghese, K. M. Hargreaves, L. A. Devi, et al. (2012)
Mol. Pharmacol. 81, 264-272
   Abstract »    Full Text »    PDF »
The Significance of G Protein-Coupled Receptor Crystallography for Drug Discovery.
J. A. Salon, D. T. Lodowski, and K. Palczewski (2011)
Pharmacol. Rev. 63, 901-937
   Abstract »    Full Text »    PDF »
Heteromerization of the {micro}- and {delta}-Opioid Receptors Produces Ligand-Biased Antagonism and Alters {micro}-Receptor Trafficking.
L. Milan-Lobo and J. L. Whistler (2011)
J. Pharmacol. Exp. Ther. 337, 868-875
   Abstract »    Full Text »    PDF »
G Protein Activation by Serotonin Type 4 Receptor Dimers: EVIDENCE THAT TURNING ON TWO PROTOMERS IS MORE EFFICIENT.
L. P. Pellissier, G. Barthet, F. Gaven, E. Cassier, E. Trinquet, J.-P. Pin, P. Marin, A. Dumuis, J. Bockaert, J.-L. Baneres, et al. (2011)
J. Biol. Chem. 286, 9985-9997
   Abstract »    Full Text »    PDF »
N-naphthoyl-{beta}-naltrexamine (NNTA), a highly selective and potent activator of {micro}/{kappa}-opioid heteromers.
A. S. Yekkirala, M. M. Lunzer, C. R. McCurdy, M. D. Powers, A. E. Kalyuzhny, S. C. Roerig, and P. S. Portoghese (2011)
PNAS 108, 5098-5103
   Abstract »    Full Text »    PDF »
Opioid-induced Down-Regulation of RGS4: ROLE OF UBIQUITINATION AND IMPLICATIONS FOR RECEPTOR CROSS-TALK.
Q. Wang and J. R. Traynor (2011)
J. Biol. Chem. 286, 7854-7864
   Abstract »    Full Text »    PDF »
G-protein-coupled receptor heteromer dynamics.
J.-P. Vilardaga, L. F. Agnati, K. Fuxe, and F. Ciruela (2010)
J. Cell Sci. 123, 4215-4220
   Abstract »    Full Text »    PDF »
Allostery at G Protein-Coupled Receptor Homo- and Heteromers: Uncharted Pharmacological Landscapes.
N. J. Smith and G. Milligan (2010)
Pharmacol. Rev. 62, 701-725
   Abstract »    Full Text »    PDF »
Oligomerization of TAS2R Bitter Taste Receptors.
C. Kuhn, B. Bufe, C. Batram, and W. Meyerhof (2010)
Chem Senses 35, 395-406
   Abstract »    Full Text »    PDF »
Seven Transmembrane Receptors as Shapeshifting Proteins: The Impact of Allosteric Modulation and Functional Selectivity on New Drug Discovery.
T. Kenakin and L. J. Miller (2010)
Pharmacol. Rev. 62, 265-304
   Abstract »    Full Text »    PDF »
An in vivo demonstration of functional G protein-coupled receptor dimers.
G. Vassart (2010)
PNAS 107, 1819-1820
   Full Text »    PDF »
Signal transduction of the CB1 cannabinoid receptor.
G. Turu and L. Hunyady (2010)
J. Mol. Endocrinol. 44, 75-85
   Abstract »    Full Text »    PDF »
Endothelin receptors: what's new and what do we need to know?.
S. W. Watts (2010)
Am J Physiol Regulatory Integrative Comp Physiol 298, R254-R260
   Abstract »    Full Text »    PDF »
Ligand- and Heterodimer-Directed Signaling of the CB1 Cannabinoid Receptor.
B. D. Hudson, T. E. Hebert, and M. E. M. Kelly (2010)
Mol. Pharmacol. 77, 1-9
   Abstract »    Full Text »    PDF »
Direct Interaction of GABAB Receptors with M2 Muscarinic Receptors Enhances Muscarinic Signaling.
S. B. Boyer, S. M. Clancy, M. Terunuma, R. Revilla-Sanchez, S. M. Thomas, S. J. Moss, and P. A. Slesinger (2009)
J. Neurosci. 29, 15796-15809
   Abstract »    Full Text »    PDF »
Prostaglandin H2 induces the migration of human eosinophils through the chemoattractant receptor homologous molecule of Th2 cells, CRTH2.
R. Schuligoi, M. Sedej, M. Waldhoer, A. Vukoja, E. M. Sturm, I. T. Lippe, B. A. Peskar, and A. Heinemann (2009)
J. Leukoc. Biol. 85, 136-145
   Abstract »    Full Text »    PDF »
Cell surface targeting of {micro}-{delta} opioid receptor heterodimers by RTP4.
F. M. Decaillot, R. Rozenfeld, A. Gupta, and L. A. Devi (2008)
PNAS 105, 16045-16050
   Abstract »    Full Text »    PDF »
Cell Growth Inhibition and Functioning of Human Somatostatin Receptor Type 2 Are Modulated by Receptor Heterodimerization.
M. Grant, H. Alturaihi, P. Jaquet, B. Collier, and U. Kumar (2008)
Mol. Endocrinol. 22, 2278-2292
   Abstract »    Full Text »    PDF »
The Role of Receptor Oligomerization in Modulating the Expression and Function of Leukocyte Adhesion-G Protein-coupled Receptors.
J. Q. Davies, G.-W. Chang, S. Yona, S. Gordon, M. Stacey, and H.-H. Lin (2007)
J. Biol. Chem. 282, 27343-27353
   Abstract »    Full Text »    PDF »
Receptor-Mediated Activation of Heterotrimeric G-Proteins: Current Structural Insights.
C. A. Johnston and D. P. Siderovski (2007)
Mol. Pharmacol. 72, 219-230
   Abstract »    Full Text »    PDF »
Selectivity of {delta}- and {kappa}-Opioid Ligands Depends on the Route of Central Administration in Mice.
M. M. Lunzer and P. S. Portoghese (2007)
J. Pharmacol. Exp. Ther. 322, 166-171
   Abstract »    Full Text »    PDF »
International Union of Basic and Clinical Pharmacology. LXVII. Recommendations for the Recognition and Nomenclature of G Protein-Coupled Receptor Heteromultimers.
J.-P. Pin, R. Neubig, M. Bouvier, L. Devi, M. Filizola, J. A. Javitch, M. J. Lohse, G. Milligan, K. Palczewski, M. Parmentier, et al. (2007)
Pharmacol. Rev. 59, 5-13
   Abstract »    Full Text »    PDF »
Orexin-1 Receptor-Cannabinoid CB1 Receptor Heterodimerization Results in Both Ligand-dependent and -independent Coordinated Alterations of Receptor Localization and Function.
J. Ellis, J. D. Pediani, M. Canals, S. Milasta, and G. Milligan (2006)
J. Biol. Chem. 281, 38812-38824
   Abstract »    Full Text »    PDF »
Oligomerization of Recombinant and Endogenously Expressed Human Histamine H4 Receptors.
R. M. van Rijn, P. L. Chazot, F. C. Shenton, K. Sansuk, R. A. Bakker, and R. Leurs (2006)
Mol. Pharmacol. 70, 604-615
   Abstract »    Full Text »    PDF »
Interactions between the Mas-Related Receptors MrgD and MrgE Alter Signalling and Trafficking of MrgD.
S. Milasta, J. Pediani, S. Appelbe, S. Trim, M. Wyatt, P. Cox, M. Fidock, and G. Milligan (2006)
Mol. Pharmacol. 69, 479-491
   Abstract »    Full Text »    PDF »
Heterodimers of {alpha}1B- and {alpha}1D-Adrenergic Receptors Form a Single Functional Entity.
C. Hague, S. E. Lee, Z. Chen, S. C. Prinster, R. A. Hall, and K. P. Minneman (2006)
Mol. Pharmacol. 69, 45-55
   Abstract »    Full Text »    PDF »
Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series.
D. J. Daniels, N. R. Lenard, C. L. Etienne, P.-Y. Law, S. C. Roerig, and P. S. Portoghese (2005)
PNAS 102, 19208-19213
   Abstract »    Full Text »    PDF »
Light Causes Phosphorylation of Nonactivated Visual Pigments in Intact Mouse Rod Photoreceptor Cells.
G. W. Shi, J. Chen, F. Concepcion, K. Motamedchaboki, P. Marjoram, R. Langen, and J. Chen (2005)
J. Biol. Chem. 280, 41184-41191
   Abstract »    Full Text »    PDF »
G Protein-coupled Receptor Kinases Promote Phosphorylation and {beta}-Arrestin-mediated Internalization of CCR5 Homo- and Hetero-oligomers.
F. Huttenrauch, B. Pollok-Kopp, and M. Oppermann (2005)
J. Biol. Chem. 280, 37503-37515
   Abstract »    Full Text »    PDF »
Diversifying the repertoire of G protein-coupled receptors through oligomerization.
P. S.-H. Park and K. Palczewski (2005)
PNAS 102, 8793-8794
   Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882