μ-Opioid receptors and regulators of G protein signaling (RGS) proteins: From a symposium on new concepts in mu-opioid pharmacology

Drug and Alcohol Dependence

Volumn 121, Issue 3, 2012, Pages 173-180

  Traynor, John ^a  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

Author keywords

G proteins; Morphine; Mu opioid receptors; RGS proteins

Indexed keywords

ENZYME ACTIVATOR; MU OPIATE RECEPTOR; REGULATOR OF G PROTEIN SIGNALLING PROTEIN 9 2; RGS PROTEIN; RGS2 PROTEIN; RGS4 PROTEIN; UNCLASSIFIED DRUG;

HUMAN; MORPHINE ADDICTION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; RECEPTOR UPREGULATION; REVIEW; SIGNAL TRANSDUCTION;

ANALGESICS, OPIOID; HUMANS; PROTEIN BINDING; RECEPTORS, OPIOID, MU; RGS PROTEINS; SIGNAL TRANSDUCTION;

EID: 84857140534     PISSN: 03768716     EISSN: 18790046     Source Type: Journal    
DOI: 10.1016/j.drugalcdep.2011.10.027     Document Type: Review

References (84)

1. Ballon D.R., Flanary P.L., Gladue D.P., Konopka J.B., Dohlman H.G., Thorner J. DEP-domain-mediated regulation of GPCR signaling responses. Cell 2006, 126:1079-1093.
2. Blazer L.L., Neubig R.R. Small molecule protein-protein interaction inhibitors as CNS therapeutic agents: current progress and future hurdles. Neuropsychopharmacology 2009, 34:126-141.
3. Blazer L.L., Roman D.L., Chung A., Larsen M.J., Greedy B.M., Husbands S.M., Neubig R.R. Reversible, allosteric small-molecule inhibitors of regulator of G protein signaling proteins. Mol. Pharmacol. 2010, 78:524-533.
4. Blazer L.L., Zhang H., Casey E.M., Husbands S.M., Neubig R.R. A nanomolar-potency small molecule inhibitor of regulator of G-protein signaling proteins. Biochemistry 2011, 50:3181-3192.
5. Bernstein L.S., Ramineni S., Hague C., Cladman W., Chidiac P., Levey A.I., Hepler J.R. RGS2 binds directly and selectively to the M1 muscarinic acetylcholine receptor third intracellular loop to modulate Gq/11alpha signaling. J. Biol. Chem. 2004, 279:21248-21256.
6. Bishop G.B., Cullinan W.E., Curran E., Gutstein H.B. Abused drugs modulate RGS4 mRNA levels in rat brain: comparison between acute drug treatment and a drug challenge after chronic treatment. Neurobiol. Dis. 2002, 10:334-343.
7. Bohn L.M., Gainetdinov R.R., Lin F.T., Lefkowitz R.J., Caron M.G. Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 2000, 408:720-723.
8. Borgland S.L. Acute opioid receptor desensitization and tolerance: is there a link?. Clin. Exp. Pharmacol. Physiol. 2001, 28:147-154.
9. Boutet-Robinet E.A., Finana F., Wurch T., Pauwels P.J., De Vries L. Endogenous RGS proteins facilitate dopamine D(2S) receptor coupling to G(alphao) proteins and Ca2+ responses in CHO-K1 cells. FEBS Lett. 2003, 533:67-71.
10. 2+ channel inhibition in rat striatal cholinergic interneurons. Proc. Natl. Acad. Sci. U.S.A. 2004, 101:16339-16344.
11. Chao J., Nestler E.J. Molecular neurobiology of drug addiction. Annu. Rev. Med. 2004, 55:113-132.
12. Chen C.K., Eversole-Cire P., Zhang H., Mancino V., Chen Y.J., He W., Wensel T.G., Simon M.I. Instability of GGL domain-containing RGS proteins in mice lacking the G protein beta-subunit Gbeta5. Proc. Natl. Acad. Sci. U.S.A. 2003, 100:6604-6609.
13. Clark M.J., Furman C.A., Gilson T.D., Traynor J.R. Comparison of the relative efficacy and potency of mu-opioid agonists to activate Galpha(i/o) proteins containing a pertussis toxin-insensitive mutation. J. Pharmacol. Exp. Ther. 2006, 317:858-864.
14. Clark M.J., Harrison C., Zhong H., Neubig R.R., Traynor J.R. Endogenous RGS protein action modulates mu-opioid signaling through Galphao. Effects on adenylyl cyclase, extracellular signal-regulated kinases, and intracellular calcium pathways. J. Biol. Chem. 2003, 278:9418-9425.
15. Clark M.J., Linderman J.J., Traynor J.R. Endogenous regulators of G protein signaling differentially modulate full and partial mu-opioid agonists at adenylyl cyclase as predicted by a collision coupling model. Mol. Pharmacol. 2008, 73:1538-1548.
16. Clark M.J., Neubig R.R., Traynor J.R. Endogenous regulator of G protein signaling proteins suppress Galphao-dependent, mu-opioid agonist-mediated adenylyl cyclase supersensitization. J. Pharmacol. Exp. Ther. 2004, 310:215-222.
17. Clark M.J., Traynor J.R. Assays for G-protein-coupled receptor signaling using RGS-insensitive Galpha subunits. Methods Enzymol. 2004, 389:155-169.
18. Clark M.J., Traynor J.R. Endogenous regulator of G protein signaling proteins reduce mu-opioid receptor desensitization and down-regulation and adenylyl cyclase tolerance in C6 cells. J. Pharmacol. Exp. Ther. 2005, 312:809-815.
19. Davydov I.V., Varshavsky A. RGS4 is arginylated and degraded by the N-end rule pathway in vitro. J. Biol. Chem. 2000, 275:22931-22941.
20. Day P.W., Tesmer J.J., Sterne-Marr R., Freeman L.C., Benovic J.L., Wedegaertner P.B. Characterization of the GRK2 binding site of Galphaq. J. Biol. Chem. 2004, 279:53643-53652.
21. Divin M.F., Bradbury F.A., Carroll F.I., Traynor J.R. Neutral antagonist activity of naltrexone and 6beta-naltrexol in naive and opioid-dependent C6 cells expressing a mu-opioid receptor. Br. J. Pharmacol. 2009, 156:1044-1053.
22. Drenan R.M., Doupnik C.A., Boyle M.P., Muglia L.J., Huettner J.E., Linder M.E., Blumer K.J. Palmitoylation regulates plasma membrane-nuclear shuttling of R7BP, a novel membrane anchor for the RGS7 family. J. Cell. Biol. 2005, 169:623-633.
23. Garnier M., Zaratin P.F., Ficalora G., Valente M., Fontanella L., Rhee M.H., Blumer K.J., Scheideler M.A. Up-regulation of regulator of G protein signaling 4 expression in a model of neuropathic pain and insensitivity to morphine. J. Pharmacol. Exp. Ther. 2003, 304:1299-1306.
24. Garzon J., Rodriguez-Munoz M., Lopez-Fando A., Sanchez-Blazquez P. The RGSZ2 protein exists in a complex with mu-opioid receptors and regulates the desensitizing capacity of Gz proteins. Neuropsychopharmacology 2005, 30:1632-1648.
25. Garzon J., Rodriguez-Munoz M., Lopez-Fando A., Garcia-Espana A., Sanchez-Blazquez P. RGSZ1 and GAIP regulate mu- but not delta-opioid receptors in mouse CNS: role in tachyphylaxis and acute tolerance. Neuropsychopharmacology 2004, 29:1091-1104.
26. Garzon J., Lopez-Fando A., Sanchez-Blazquez P. The R7 subfamily of RGS proteins assists tachyphylaxis and acute tolerance at mu-opioid receptors. Neuropsychopharmacology 2003, 28:1983-1990.
27. Garzon J., Rodriguez-Diaz M., Lopez-Fando A., Sanchez-Blazquez P. RGS9 proteins facilitate acute tolerance to mu-opioid effects. Eur. J. Neurosci. 2001, 13:801-811.
28. Georgoussi Z., Leontiadis L., Mazarakou G., Merkouris M., Hyde K., Hamm H. Selective interactions between G protein subunits and RGS4 with the C-terminal domains of the mu- and delta-opioid receptors regulate opioid receptor signaling. Cell Signal. 2006, 18:771-782.
29. Gold S.J., Han M.H., Herman A.E., Ni Y.G., Pudiak C.M., Aghajanian G.K., Liu R.J., Potts B.W., Mumby S.M., Nestler E.J. Regulation of RGS proteins by chronic morphine in rat locus coeruleus. Eur. J. Neurosci. 2003, 17:971-980.
30. Gold S.J., Ni Y.G., Dohlman H.G., Nestler E.J. Regulators of G-protein signaling (RGS) proteins: region-specific expression of nine subtypes in rat brain. J. Neurosci. 1997, 17:8024-8037.
31. Granneman J.G., Zhai Y., Zhu Z., Bannon M.J., Burchett S.A., Schmidt C.J., Andrade R., Cooper J. Molecular characterization of human and rat RGS 9L, a novel splice variant enriched in dopamine target regions, and chromosomal localization of the RGS 9 gene. Mol. Pharmacol. 1998, 54:687-694.
32. Greengard P., Allen P.B., Nairn A.C. Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Neuron 1999, 23:435-447.
33. Grillet N., Pattyn A., Contet C., Kieffer B.L., Goridis C., Brunet J.F. Generation and characterization of RGS4 mutant mice. Mol. Cell. Biol. 2005, 25:4221-4228.
34. Han M.H., Renthal W., Ring R.H., Rahman Z., Psifogeorgou K., Howland D., Birnbaum S., Young K., Neve R., Nestler E.J., Zachariou V. Brain region specific actions of regulator of G protein signaling 4 oppose morphine reward and dependence but promote analgesia. Biol. Psychiatry 2010, 67:761-769.
35. Hollinger S., Hepler J.R. Cellular regulation of RGS proteins: modulators and integrators of G protein signaling. Pharmacol. Rev. 2002, 54:527-559.
36. Hooks S.B., Martemyanov K., Zachariou V. A role of RGS proteins in drug addiction. Biochem. Pharmacol. 2008, 75:76-84.
37. Huang X., Fu Y., Charbeneau R.A., Saunders T.L., Taylor D.K., Hankenson K.D., Russell M.W., D'Alecy L.G., Neubig R.R. Pleiotropic phenotype of a genomic knock-in of an RGS-insensitive G184S Gnai2 allele. Mol. Cell. Biol. 2006, 26:6870-6879.
38. Ippolito D.L., Temkin P.A., Rogalski S.L., Chavkin C. N-terminal tyrosine residues within the potassium channel Kir3 modulate GTPase activity of Galphai. J. Biol. Chem. 2002, 277:32692-32696.
39. Jabourian M., Venance L., Bourgoin S., Ozon S., Pérez S., Godeheu G., Glowinski J., Kemel M.-L. Functional mu opioid receptors are expressed in cholinergic interneurons of the rat dorsal striatum: territorial specificity and diurnal variation. Eur. J. Neurosci. 2005, 12:3301-3309.
40. Kenakin T. Pharmacologic Analysis of Drug-Receptor Interactions 1997, Raven press, New York. 2nd ed.
41. Koob G.F., Sanna P.P., Bloom F.E. Neuroscience of addiction. Neuron 1998, 21:467-476.
42. 13. Science 1998, 280:53643-53652.
43. Lan K.L., Sarvazyan N.A., Taussig R., Mackenzie R.G., DiBello P.R., Dohlman H.G., Neubig R.R. A point mutation in Galphao and Galphai1 blocks interaction with regulator of G protein signaling proteins. J. Biol. Chem. 1998, 273:12794-12797.
44. Lan K.L., Zhong H., Nanamori M., Neubig R.R. Rapid kinetics of regulator of G-protein signaling (RGS)-mediated Galphai and Galphao deactivation. Galpha specificity of RGS4 AND RGS7. J. Biol. Chem. 2000, 275:33497-33503.
45. Laugwitz K.L., Offermanns S., Spicher K., Schultz G. Mu and delta opioid receptors differentially couple to G protein subtypes in membranes of human neuroblastoma SH-SY5Y cells. Neuron 1993, 10:233-242.
46. Leontiadis L.J., Papakonstantinou M.P., Georgoussi Z. Regulator of G protein signaling 4 confers selectivity to specific G proteins to modulate mu- and delta-opioid receptor signaling. Cell Signal. 2009, 21:1218-1228.
47. Lopez-Fando A., Rodriguez-Munoz M., Sanchez-Blazquez P., Garzon J. Expression of neural RGS-R7 and Gβ5 proteins in response to acute and chronic morphine. Neuropsychopharmacology 1995, 30:99-110.
48. Mansour A., Fox C.A., Burke S., Akil H., Watson S.J. Immunohistochemical localization of the cloned mu opioid receptor in the rat CNS. J. Chem. Neuroanat. 1995, 8:283-305.
49. Martemyanov K.A., Yoo P.J., Skiba N.P., Arshavsky V.Y. R7BP, a novel neuronal protein interacting with RGS proteins of the R7 family. J. Biol. Chem. 2005, 280:5133-5136.
50. Nakagawa T., Minami M., Satoh M. Up-regulation of RGS4 mRNA by opioid receptor agonists in PC12 cells expressing cloned mu- or kappa-opioid receptors. Eur. J. Pharmacol. 2001, 433:29-36.
51. Nomoto S., Adachi K., Yang L.X., Hirata Y., Muraguchi S., Kiuchi K. Distribution of RGS4 mRNA in mouse brain shown by in situ hybridization. Biochem. Biophys. Res. Commun. 1997, 241:281-287.
52. Papachatzaki M.M., Antal Z., Terzi D., Szucs P., Zachariou V., Antal M. RGS9-2 modulates nociceptive behaviour and opioid-mediated synaptic transmission in the spinal dorsal horn. Neurosci. Lett. 2011, 501:31-34.
53. Posner B.A., Gilman A.G., Harris B.A. Regulators of G protein signaling 6 and 7. Purification of complexes with Gbeta5 and assessment of their effects on G protein-mediated signaling pathways. J. Biol. Chem. 1999, 274:31087-31093.
54. Potenza M.N., Gold S.J., Roby-Shemkowitz A., Lerner M.R., Nestler E.J. Effects of regulators of G protein-signaling proteins on the functional response of the mu-opioid receptor in a melanophore-based assay. J. Pharmacol. Exp. Ther. 1999, 291:482-491.
55. Psifogeorgou K., Terzi D., Papachatzaki M.M., Varidaki A., Ferguson D., Gold S.J., Zachariou V. A unique role of RGS9-2 in the striatum as a positive or negative regulator of opiate analgesia. J. Neurosci. 2011, 31:5617-5624.
56. Psifogeorgou K., Papakosta P., Russo S.J., Neve R.L., Kardassis D., Gold S.J., Zachariou V. RGS9-2 is a negative modulator of mu-opioid receptor function. J. Neurochem. 2007, 103:617-625.
57. Rahman Z., Schwarz J., Gold S.J., Zachariou V., Wein M.N., Choi K.H., Kovoor A., Chen C.K., DiLeone R.J., Schwarz S.C., Selley D.E., Sim-Selley L.J., Barrot M., Luedtke R.R., Self D., Neve R.L., Lester H.A., Simon M.I., Nestler E.J. RGS9 modulates dopamine signaling in the basal ganglia. Neuron 2003, 38:941-952.
58. Roman D.L., Talbot J.N., Roof R.A., Sunahara R.K., Traynor J.R., Neubig R.R. Identification of small-molecule inhibitors of RGS4 using a high-throughput flow cytometry protein interaction assay. Mol. Pharm. 2007, 71:169-175.
59. Saitoh O., Murata Y., Odagiri M., Itoh M., Itoh H., Misaka T., Kubo Y. Alternative splicing of RGS8 gene determines inhibitory function of receptor type-specific Gq signaling. Proc. Natl. Acad. Sci. U.S.A. 2002, 99:10138-10143.
60. Song J.H., Waataja J.J., Martemyanov K.A. Subcellular targeting of RGS9-2 is controlled by multiple molecular determinants on its membrane anchor, R7BP. J. Biol. Chem. 2006, 281:15361-15369.
61. Talbot J.N., Jutkiewicz E.M., Graves S.M., Clemans C.F., Nicol M.R., Mortensen R.M., Huang X., Neubig R.R., Traynor J.R. RGS inhibition at G(alpha)i2 selectively potentiates 5-HT1A-mediated antidepressant effects. Proc. Natl. Acad. Sci. U.S.A. 2010, 107:11086-11091.
62. Talbot J.N., Roman D.L., Clark M.J., Roof R.A., Tesmer J.J., Neubig R.R., Traynor J.R. Differential modulation of mu-opioid receptor signaling to adenylyl cyclase by regulators of G protein signaling proteins 4 or 8 and 7 in permeabilised C6 cells is Galpha subtype dependent. J. Neurochem. 2010, 112:1026-1034.
63. Tesmer J.J., Berman D.M., Gilman A.G., Sprang S.R. Structure of RGS4 bound to AlF4-activated G(i alpha1): stabilization of the transition state for GTP hydrolysis. Cell 1997, 89:251-261.
64. Traynor J.R. G protein coupling and efficacy of mu-opioid agonists: relationship to behavioral efficacy. Revs. Anesth. 2004, 8:11-22.
65. Traynor J. Regulator of G protein-signaling proteins and addictive drugs. Ann. N.Y. Acad. Sci. 2010, 1187:341-352.
66. Traynor J.R., Neubig R.R. Regulators of G protein signaling and drugs of abuse. Mol. Interv. 2005, 5:30-41.
67. Traynor J.R., Terzi D., Caldarone B.J., Zachariou V. RGS9-2: probing an intracellular modulator of behavior as a drug target. Trends Pharmacol. Sci. 2009, 30:105-111.
68. von Zastrow M. Regulation of opioid receptors by endocytic membrane traffic: mechanisms and translational implications. Drug Alcohol Depend. 2010, 108:166-171.
69. Wang H., Moriwaki A., Wang J.B., Uhl G.R., Pickel V.P. Ultrastructural immunocytochemical localization of mu-opioid receptors in dendritic targets of dopaminergic terminals in the rat caudate-putamen nucleus. Neuroscience 1997, 81:757-771.
70. Wang Q., Liu-Chen L.Y., Traynor J.R. Differential modulation of mu- and delta-opioid receptor agonists by endogenous RGS4 protein in SH-SY5Y cells. J. Biol. Chem. 2009, 284:18357-18367.
71. Wang Q., Liu M., Mullah B., Siderovski D.P., Neubig R.R. Receptor-selective effects of endogenous RGS3 and RGS5 to regulate mitogen-activated protein kinase activation in rat vascular smooth muscle cells. J. Biol. Chem. 2002, 277:24949-24958.
72. Wang Q., Traynor J.R. Opioid-induced down-regulation of RGS4: role of ubiquitination and implications for receptor cross-talk. J. Biol. Chem. 2011, 286:7854-7864.
73. 2+ signalling by binding the N-terminal domain of RGS2 and the third intracellular loop of G-protein-coupled receptors. Nat. Cell. Biol. 2005, 7:405-411.
74. Watts V.J. Molecular mechanisms for heterologous sensitization of adenylate cyclase. J. Pharmacol. Exp. Ther. 2002, 302:1-7.
75. Welsby P.J., Kellett E., Wilkinson G., Milligan G. Enhanced detection of receptor constitutive activity in the presence of regulators of G protein signaling: applications to the detection and analysis of inverse agonists and low-efficacy partial agonists. Mol. Pharmacol. 2002, 61:1211-1221.
76. Witherow D.S., Wang Q., Levay K., Cabrera J.L., Chen J., Willars G.B., Slepak V.Z. Complexes of the G protein subunit Gbeta 5 with the regulators of G protein signaling RGS7 and RGS9. Characterization in native tissues and in transfected cells. J. Biol. Chem. 2000, 275:24872-24880.
77. Xie Z., Li Z., Guo L., Ye C., Li J., Yu X., Yang H., Wang Y., Chen C., Zhang D., Liu-Chen L.Y. Regulator of G protein signaling proteins differentially modulate signaling of mu and delta opioid receptors. Eur. J. Pharmacol. 2007, 565:45-53.
78. Xu X., Zeng W., Popov S., Berman D.M., Davignon I., Yu K., Yowe D., Offermanns S., Muallem S., Wilkie T.M. RGS proteins determine signaling specificity of Gq-coupled receptors. J. Biol. Chem. 1999, 274:3549-3556.
79. Zachariou V., Georgescu D., Sanchez N., Rahman Z., DiLeone R., Berton O., Neve R.L., Sim-Selley L.J., Selley D.E., Gold S.J., Nestler E.J. Essential role for RGS9 in opiate action. Proc. Natl. Acad. Sci. U.S.A. 2003, 100:13656-13661.
80. Zachariou V., Liu R., LaPlant Q., Xiao G., Renthal W., Chan G.C., Storm D.R., Aghajanian G., Nestler E.J. Distinct roles of adenylyl cyclases 1 and 8 in opiate dependence: behavioral, electrophysiological, and molecular studies. Biol. Psychiatry 2008, 63:1013-1021.
81. Zeng W., Xu X., Popov S., Mukhopadhyay S., Chidiac P., Swistok J., Danho W., Yagaloff K.A., Fisher S.L., Ross E.M., Muallem S., Wilkie T.M. The N-terminal domain of RGS4 confers receptor-selective inhibition of G protein signaling. J. Biol. Chem. 1998, 273:34687-34690.
82. Zheng B., De Vries L., Gist Farquhar M. Divergence of RGS proteins: evidence for the existence of six mammalian RGS subfamilies. Trends Biochem. Sci. 1999, 24:411-414.
83. Zhong H., Neubig R.R. Regulator of G protein signaling proteins: novel multifunctional drug targets. J. Pharmacol. Exp. Ther. 2001, 297:837-845.
84. Zhong H., Wade S.M., Woolf P.J., Linderman J.J., Traynor J.R., Neubig R.R. A spatial focusing model for G protein signals. Regulator of G protein signaling (RGS) protein-mediated kinetic scaffolding. J. Biol. Chem. 2003, 278:7278-7284.