Advertisement

The AAPS Journal

, Volume 8, Issue 1, pp E153–E159 | Cite as

Targeting opioid receptor heterodimers: Strategies for screening and drug development

  • Achla Gupta
  • Fabien M. Décaillot
  • Lakshmi A. Devi
Article

Abstract

G-protein-coupled receptors are a major target for the development of new marketable drugs. A growing number of studies have shown that these receptors could bind to their ligands, signal, and be internalized as dimers. Most of the evidence comes from in vitro studies, but recent studies using animal models support an important role for dimerization in vivo and in human pathologies. It is therefore becoming highly relevant to include dimerization in screening campaigns: the increased complexity reached by the ability to target 2 receptors should lead to the identification of more specific hits that could be developed into drugs with fewer side effects. In this review, we have summarized results from a series of studies characterizing the properties of G-protein-coupled receptor dimers using both in vitro and in vivo systems. Since opioid receptors exist as dimers and heterodimerization modulates their pharmacology, we have used them as a model system to develop strategies for the identification of compounds that will specifically bind and activate opioid receptor heterodimers: such compounds could represent the next generation of pain relievers with decreased side effects, including reduced drug abuse liability.

Keywords

G-protein-coupled receptors dimerization, allosteric interaction high-throughput screening (HTS) secreted alkaline phosphatase (SEAP) 

References

  1. 1.
    Kieffer BL. Recent advances in molecular recognition and signal transduction of active peptides: receptors for opioid peptides.Cell Mol Neurobiol. 1995;15:615–635.CrossRefPubMedGoogle Scholar
  2. 2.
    George SR, O'Dowd BF, Lee SP. G-protein-coupled receptor oligomerization and its potential for drug discovery.Nat Rev Drug Discov 2002;1:808–820.CrossRefPubMedGoogle Scholar
  3. 3.
    Maggio R, Vogel Z, Wess J. Coexpression studies with mutant muscarinic/adrenergic receptors provide evidence for intermolecular “cross-talk” between G-protein linked-receptors.Proc Natl Acad Sci USA. 1993;90:3103–3107.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Rios CD, Jordan BA, Gomes I, Devi LA. G-protein receptor dimerization: modulation of receptor function.Pharmacol Ther. 2001;92:71–87.CrossRefPubMedGoogle Scholar
  5. 5.
    Angers S, Salahpour A, Bouvier M. Dimerization: an emerging concept for G-protein coupled receptor ontogeny and function.Annu Rev Pharmacol Toxicol. 2002;42:409–435.CrossRefPubMedGoogle Scholar
  6. 6.
    Bai M. Dimerization of G-protein coupled receptors: roles in signal transduction.Cell Signal. 2004;16:175–186.CrossRefPubMedGoogle Scholar
  7. 7.
    Kroeger KM, Pfleger KD, Eidne KA. G-protein coupled receptor oligomerization in neuroendocrine pathways.Front Neuroendocrinol. 2003;24:254–278.CrossRefPubMedGoogle Scholar
  8. 8.
    Marshall FH, Jones KA, Kaupman K, Bettler B. GABA(B) receptors: the first 7TM heterodimers.Trends Pharmacol Sci. 1999;20:396–399.CrossRefPubMedGoogle Scholar
  9. 9.
    Gomes I, Devi LA. Receptor-receptor interactions modulate opioid receptor function. In: Madras BH, Colvis CM, Pollock D, Rutter JL, Shurtleff D, Von Zastrow M, eds.Cell Biology of Addiction. New York, NY: Cold Spring Harbor Laboratory Press, 2005.Google Scholar
  10. 10.
    Bouvier M. Oligomerization of G-protein-coupled transmitter receptors.Nat Rev Neurosci. 2001;2:274–286.CrossRefPubMedGoogle Scholar
  11. 11.
    Jordan BA, Devi LA. G-protein coupled receptor heterodimerization modulates receptor function.Nature. 1999;399:697–700.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Gomes, I, Jordan BA, Gupta A, Trapaidze N, Nagy V, Devi LA. Heterodimerization of mu and delta opioid receptors: a role in opiate synergy.J Neurosci. 2000;20:RC110.PubMedPubMedCentralGoogle Scholar
  13. 13.
    George SR, Fan T, Xie Z, et al. Oligomerization of mu and delta opioid receptors: generation of novel functional properties.J Biol Chem. 2000;275:26128–26135.CrossRefPubMedGoogle Scholar
  14. 14.
    Gomes I, Gupta A, Filipovska J, Szeto HH, Pintar JE, Devi LA. A role for heterodimerization of μ and δ opiate receptors in enhancing morphine analgesia.Proc Natl Acad Sci USA. 2004;101: 5135–5139.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Pfeiffer M, Koch T, Schroder H, Laugsch M, Hollt V, Schulz S. Heterodimerization of somatostatin and opioid receptors cross-modulates phosphorylation, internalization, and desensitization.J Biol Chem. 2002;277:19762–19772.CrossRefPubMedGoogle Scholar
  16. 16.
    Jordan BA, Gomes I, Rios C, Filipovska J, Devi LA. Functional interactions between μ opioid and α2A-adrenergic receptors.Mol Pharmacol. 2003;64:1317–1324.CrossRefPubMedGoogle Scholar
  17. 17.
    Rios C, Gomes I, Devi LA. Interactions between delta opioid receptors and alpha-adrenoceptors.Clin Exp Pharmacol Physiol. 2004;31:833–836.CrossRefPubMedGoogle Scholar
  18. 18.
    Pfeiffer M, Kirscht S, Stumm R, et al. Heterodimerization of substance P and mu-opioid receptors regulates receptor trafficking and resensitization.J Biol Chem. 2003;278:51630–51637.CrossRefPubMedGoogle Scholar
  19. 19.
    Fotiadis D, Liang Y, Filipek S, Saperstein DA, Engel A, Palczewski K. Atomic-force microscopy: rhodopsin dimmers in native disc membranes.Nature. 2003;421:127–128.CrossRefPubMedGoogle Scholar
  20. 20.
    AbdAlla S, Lother H, Quitterer U. AT1-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration.Nature. 2000;407;91–98.Google Scholar
  21. 21.
    Abdalla S, Lother H, el Massiery A, Quitterer U. Increased AT(1) receptor hetero dimers in preeclampsia mediate enhanced angiotensin II responsiveness.Nat Med. 2001;7:1003–1009.CrossRefPubMedGoogle Scholar
  22. 22.
    Abdalla S, Lother H, Langer A, el Faramawy Y, Quitterer U. Factor XIIIA transglutaminase crosslinks AT1 receptor dimers of monocytes at the onset of atherosclerosis.Cell. 2004;119:343–354.CrossRefPubMedGoogle Scholar
  23. 23.
    Murtra P, Sheasby AM, Hunt SP, De Felipe C. Rewarding effects of opiates are absent in mice lacking the receptor for substance P.Nature. 2000;405:180–183.CrossRefPubMedGoogle Scholar
  24. 24.
    King T, Gardell LR, Wang R, et al. Role of NK-1 neurotransmission in opioid-induced hyperalgesia.Pain. 2005;116:276–288.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Hunyady L, Vauquelin G, Vanderheyden P. Agonist induction and conformational selection during activation of a G-protein-coupled receptor.Trends Pharmacol Sci. 2003;24:81–86.CrossRefPubMedGoogle Scholar
  26. 26.
    Cherfils J, Chabre M. Activation of G-protein Galpha subunits by receptors through Galpha-Gbeta and Galpha-Ggamma interactions.Trends Biochem Sci. 2003;28:13–17.CrossRefPubMedGoogle Scholar
  27. 27.
    Urwyler S, Pozza MF, Lingenhoehl K, et al. N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and structurally related compounds: novel allosteric enhancers of gamma-aminobutyric acidB receptor function.J Pharmacol Exp Ther. 2003;307:322–330.CrossRefPubMedGoogle Scholar
  28. 28.
    Cryan JF, Kaupmann K. Don't worry ‘B’ happy!: a role for GABA(B) receptors in anxiety and depression.Trends Pharmacol Sci. 2005;26:36–43.CrossRefPubMedGoogle Scholar
  29. 29.
    Binet V, Brajon C, Le Corre L, Acher F, Pin JP, Prezeau L. The heptahelical domain of GABA(B2) is activated directly by CGP7930 a positive allosteric modulator of the GABA(B) receptor.J Biol Chem. 2004;279:29085–29091.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Cryan JF, Kelly PH, Chaperon F, et al. Behavioral characterization of the novel GABAB receptor-positive modulator GS39783 (N,N′-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): anxiolytic-like activity without side effects associated with baclofen or benzodiazepines.J Pharmacol Exp Ther. 2004;310:952–963.CrossRefPubMedGoogle Scholar
  31. 31.
    Knoflach F, Mutel V, Jolidon S, et al. Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site.Proc Natl Acad Sci USA. 2001;98:13402–13407.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Conigrave AD, Franks AH. Allosteric activation of plasma membrane receptors: physiological implications and structural origins.Prog Biophys Mol Biol. 2003;81:219–240.CrossRefPubMedGoogle Scholar
  33. 33.
    Suzuki Y, Moriyoshi E, Tsuchiya D, Jingami H. Negative cooperativity of glutamate binding in the dimeric metabotropic glutamate receptor subtype I.J Biol Chem. 2004;279:35526–35534.CrossRefPubMedGoogle Scholar
  34. 34.
    Gao ZG, Kim SG, Soltysiak KA, Melman N, Ijzerman AP, Jacobson KA. Selective allosteric enhancement of agonist binding and function at human A3 adenosine receptors by a series of imidazoquinoline derivatives.Mol Pharmacol. 2002;62:81–89.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Trankle C, Weyand O, Voigtlander U, et al. Interactions of orthosteric and allosteric ligands with [3H]dimethyl-W84 at the common allosteric site of muscarinic M2 receptors.Mol Pharmacol. 2003;64:180–190.CrossRefPubMedGoogle Scholar
  36. 36.
    Gille A, Seifert R. Low-affinity interactions of BODIPY-FL-GTPgammaS and BODIPY-FL-GppNHp with G(i)- and G(s)-proteins.Naunyn Schmiedebergs Arch Pharmacol. 2003;368:210–215.CrossRefPubMedGoogle Scholar
  37. 37.
    Lembo PM, Grazzini E, Groblewski T, et al. Proenkephalin A gene products activate a new family of sensory neuron-specific GPCRs.Nat Neurosci. 2002;5:201–209.CrossRefPubMedGoogle Scholar
  38. 38.
    Cacace A, Banks M, Spicer T, Civoli F, Watson J. An ultra-HTS process for the identification of small molecule modulators of orphan G-protein-coupled receptors.Drug Discov Today. 2003;8:785–792.CrossRefPubMedGoogle Scholar
  39. 39.
    Chen L, Zou S, Lou X, Kang HG. Different stimulatory opioid effects on intracellular Ca(2+) in SH-SY5Y cells.Brain Res. 2000;882:256–265.CrossRefPubMedGoogle Scholar
  40. 40.
    Yoon SH, Lo TM, Loh HH, Thayer SA. Delta-opioid-induced liberation of Gbetagamma mobilizes Ca2+ stores in NG108-15 cells.Mol Pharmacol. 1999;56:902–908.PubMedGoogle Scholar
  41. 41.
    Charles AC, Mostovskaya N, Asas K, Evans CJ, Dankovich ML, Hales TG. Coexpression of delta-opioid receptors with micro receptors in GH3 cells changes the functional response to micro agonists from inhibitory to excitatory.Mol Pharmacol. 2003;63:89–95.CrossRefPubMedGoogle Scholar
  42. 42.
    Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors.Annu Rev Biochem. 2004;73:953–990.CrossRefPubMedGoogle Scholar
  43. 43.
    Schiller PW, Weltrowska G, Berezowska I, et al. The TIPP opioid peptide family: development of delta antagonists, delta agonists, and mixed mu agonist/delta antagonists.Biopolymers. 1999;51:411–425.CrossRefPubMedGoogle Scholar
  44. 44.
    Bryant SD, Salvadori S, Cooper PS, Lazarus LH. New delta-opioid antagonists as pharmacological probes.Trends Pharmacol Sci. 1998;19:42–46.CrossRefPubMedGoogle Scholar
  45. 45.
    Durocher Y, Perret S, Thibaudeau E, et al. A reporter gene assay for high-throughput screening of G-protein-coupled receptors stably or transiently expressed in HEK293 EBNA cells grown in suspension culture.Anal Biochem. 2000;284:316–326.CrossRefPubMedGoogle Scholar
  46. 46.
    Waldhoer M, Fong J, Jones RM, et al. A heterodimer-selective agonist shows in vivo releavance of G protein-coupled receptor dimers.Proc Natl Acad Sci USA. 2005;102:9050–9055.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Mesnier D, Baneres JL. Cooperative conformational changes in a G-protein-coupled receptor dimer, the leukotriene B(4) receptor BLT1.J Biol Chem. 2004;279:49664–49670.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2006

Authors and Affiliations

  • Achla Gupta
    • 1
  • Fabien M. Décaillot
    • 1
  • Lakshmi A. Devi
    • 1
  1. 1.Department of Pharmacology and Biological ChemistryMount Sinai School of MedicineNew York

Personalised recommendations