Dopamine receptors

Overview

Dopamine, the predominant catecholamine transmitter in the central nervous system (CNS), controls different functions, including locomotor activity, attention, motivation and positive reinforcement, cognitive functions, hormonal regulation, cardiovascular, renal and gastrointestinal... [read more] functions by interacting with a family of G protein-coupled receptors (GPCR) coded by five distinct genes.

The existence of two types of dopamine receptors was first proposed in 1978 and 1979 on the basis of pharmacological and functional studies [1,2]. In particular the receptor that stimulates adenylyl cyclase and has low affinity for the antipsychotic drug sulpiride was referred to as the D₁ while D₂ was the receptor that inhibits cAMP formation and has high affinity for sulpiride [1,2]. That there were only two types of dopamine receptors was the dogma for over a decade. Then, beginning with the publication of the dopamine D₂ receptor sequence in 1988 [3] subsequent gene cloning studies revealed the existence of 5 different genes that code for 5 distinct dopamine receptor subtypes- now referred to as D₁, D₂, D₃, D₄ and D₅, and numerous isoforms generated by alternative splicing. Sequence analysis, pharmacological studies and evaluation of their ability to either stimulate or inhibit cAMP formation by coupling to Gαs/olf or Gαi/o proteins, however, reveal that all cloned dopamine receptor subtypes heterologously expressed in tissue culture cells can be grouped into one of the two initially recognized receptor categories. Dopamine receptors were thus divided into the D₁-like and D₂-like families (reviewed in [4,5,6,7,8]). D₁-like receptors genes are intronless in their amino acid coding region and include D₁ and D₅ subtypes in mammals, as well as a third subtype in lower organisms [9]. The D₂-like receptors include the D₂, D₃ and D₄ subtypes. In mammals, the protein coding regions of the D₂-like receptors contain introns and different isoforms have been identified as a result of alternative splicing (reviewed in [4,5,6,7,8]). In particular two D₂ receptor isoforms (D₂-short and D₂-long) have been identified, that differ in the presence or absence of a 29-amino acid domain in the third intracellular loop (reviewed in [4,5,6,7]) and display specific functional and signaling properties [10,11,12,13]. Splice variants of the D₃ receptor and polymorphic variants of the D₄ receptor have also been identified (reviewed in [6,7].

The identification of the five dopamine receptor subtypes, each with unique localization and properties, stimulated the effort to develop subtype-selective drugs to treat specific symptoms for disorders associated with dopaminergic dysfunctions, including Parkinson’s disease and schizophrenia. In particular, D₂-like preferring agonists such as pramipexole, ropinirole, piribedil, rotigotine, and the ergot alkaloids pergolide, bromocriptine and cabergoline have proven useful for the therapy of Parkinson’s disease. Pergolide, ropinirole, pramipexole and rotigotine have a significant degree of selectivity for D₂-like over D₁-like dopamine receptors, and ropinirole, pramipexole, and rotigotine have higher affinity for the D₃ vs. the D₂ receptor [14,15]. Overstimulation of D₁ receptor-mediated signaling in the striatum has been associated with the development of L-DOPA-induced dyskinesias in animal models of Parkinson’s disease [16,17,18,19]; the low affinity of D₂/D₃ agonists for the D₁ receptor may be related to the low incidence of motor side effects of these drugs.

The mesocorticolimbic dopamine system is implicated in schizophrenia. A strong correlation exists, in fact, between the therapeutic effects of antipsychotics and blockade of the D₂ dopamine receptor. Notably, all clinically approved antipsychotics are D₂ receptor blockers. The second and third generation of antipsychotics, that target other receptors such as the serotonin 5-HT_2A, and have a lower incidence of side effects, still possess antagonistic activity at D₂ receptors [20] (and reviewed in [21]).

Evidence accumulating through the study of dopamine receptor signaling in the last ten years has pointed to a further degree of complexity within these receptor families. The canonical paradigm of dopamine receptor activation and signalling involves the sequential activation of G proteins and specific enzyme or channel effectors. However, this model is too simplistic to explain the functional flexibility of these receptors. It is now widely accepted that dopamine receptor signaling is not limited to activation or inhibition of adenylyl cyclase, but that dopamine receptors regulate multiple signaling pathways by interacting with various G proteins, by activating G protein-independent mechanisms and by interacting with ion channels and tyrosine kinase receptors (for review, see [21]).

The classical view of dopamine receptor signaling implies that the D₁ receptor stimulates the cAMP/PKA/DARPP-32 pathway [22,23,24] while the D₂ and, to a lesser extent, the D₃ receptors inhibit this pathway (reviewed in [7]). More recent data suggest that activation of DARPP-32 results in inhibition of PP1 and activation of the mTOR complex 1 (mTORC1) leading to rpS6 phosphorylation [16,25,26,27]. Moreover, D₁ receptor-mediated PKA activation also results in the activation of the extracellular signal-regulated kinases 1/2 (Erk1/2) by two mechanisms: src-Shp2-dependent Erk1/2 phosphorylation [18,28] and DARPP-32-mediated inhibition of protein phosphatase-1 [27]. It is believed that upregulation of these mechanisms, leading to aberrant Erk1/2 activation, are involved in the development of L-DOPA-induced dyskinesias in animal models of Parkinson’s disease [16,17,18,29]. Both D₁-like and D₂-like receptors also signal through alternative cAMP-independent pathways. In particular, there is evidence that D₁ and D₂ receptors modulate calcium channel activity by direct protein-protein interactions [30] (and reviewed in [21]) and that the D₁ and D₂ receptors modulate the Na⁺-K⁺ ATPase [31,32]. Moreover, both D₁-like and D₂-like receptors transactivate tyrosine kinase receptors [33,34,35,37,38,39]. D₂ and D₃ receptors also regulate calcium and potassium channel activity and activate PI-3K leading to Akt and Erk activation by a Gβγ-mediated mechanism [22,40,41,42].

The paradigm that dopamine receptors signal through G proteins has been recently unsettled by the observation that the D₂ receptor may transduce signaling through G protein-independent, arrestin 2/3 (β-arrestin)-mediated mechanisms [21,22,43,44]. Beside their role in GPCR desensitization and internalization, arrestin 2 (β-arrestin1) and arrestin 3 (β-arrestin2), in fact, can act as molecular scaffolds for signaling effectors (reviewed in [21,22,43,44,45]). In particular, D₂ receptor agonists promote the clustering of the D₂ receptor, arrestin 2 (β-arrestin2), Akt and PP-2A into a molecular complex that allows PP-2A to dephosphorylate and inactivate Akt resulting in GSK3 activation ([21,22,43,44,46,47]. Modulation of the formation of this complex may represent a new mechanism to explain the effects of D₂-related drugs. For example, it has been reported that lithium acts by inducing the dissociation of the D₂/Akt/arrestin/PP-2A complex [48,49,50,51,52] and that all antipsychotics prevent agonist-induced arrestin 2/3 (β-arrestin) recruitment to the D₂ receptor [53].

Another level of complexity involving dopamine receptors has been pointed out by evidence that, like many other GPCRs, dopamine receptors directly interact with members of the same family and with structurally divergent families of receptors to form heteromers with pharmacological, signaling and trafficking properties different from those of their constituent receptors (reviewed in [54,55,56]). Since heteromers represent novel receptor entities working as unique functional units, heteromerization, providing different combinatorial possibilities, increases heterogeneity within dopamine receptor subtypes. Along this line, heteromers formed by D₁ and D₂ receptors [58,59,60,61,62,63], D₁ and D₃ receptors [65,66,67], D₂ and D₃ receptors [68,69], D₁ and adenosine A₁ receptors [70,71], D₁ and glutamate NMDA receptors [72,73,74,75], D₂ and adenosine A_2A receptors [76,77], D₂ and trace amine TAAR1 [78,79] have been identified and characterized in the last ten years. High order heteromers such as D₂/mGluR₅/A_2A receptors [80] and D₂/A_2A/CB₁ [81] have also been identified by sequential BRET-FRET. These are only a few examples of heteromers containing dopamine receptors and many other complexes have been identified (reviewed in [21]).

The recent discovery of D₂ receptor signaling heterogeneity has led to a reconsideration of the mechanism(s) of action of some antipsychotics [50] and to the development of “biased drugs” to selectively target arrestin 3 (β-arrestin2)-mediated D₂ signaling in schizophrenia. This pathway is thought to significantly contribute to the effects of antipsychotics. In particular, all antipsychotics efficiently prevent agonist-induced arrestin 2/3 (β-arrestin) recruitment to the D₂ receptor [53], while variably influencing D₂-mediated inhibition of cAMP formation. For example, aripiprazole is a partial agonist for D₂-related cAMP signaling and a full antagonist for the recruitment of arrestin 3 (β-arrestin2) to the D₂R. This observation led to the development of compounds UNC9975, UNC0006 and UNC9994 that could represent the first attempt to develop partially biased agonists for the D₂/arrestin/Akt/PP-2A pathway [82] (reviewed in [21]). These compounds bind to the D₂ receptor and act as partial agonists for arrestin 3 (β-arrestin2) recruitment to D₂ receptor, but are antagonists of cAMP signaling.

The discovery of the existence of dopamine receptor heteromers with atypical properties also opens the way to the development of new drugs. Receptor heteromers could represent, in fact, potential and promising targets for bifunctional compounds selectively acting on the complex or allosteric ligands that, by interacting with one co-receptor modify the function of the other co-receptor, or small molecules that can disrupt heteromeric complexes.

Taken together, the newly discovered aspects of dopamine receptor function might represent a breakthrough for the development of innovative drugs for the treatment of a variety of dopamine-related neurological and neuropsychiatric disorders.

References

1. Spano PF, Govoni S, Trabucchi M. Studies on the pharmacological properties of dopamine receptors in various areas of the central nervous system. Adv Biochem Psychopharmacol 1978;19:155-65.
2. Kebabian JW, Calne DB. Multiple receptors for dopamine. Nature 1979;277:93-6.
3. Bunzow JR, Van Tol HH, Grandy DK, et al. Cloning and expression of a rat D2 dopamine receptor cDNA. Nature 1988;336:783-7.
4. Sibley DR, Monsma Jr FJ. Molecular biology of dopamine receptors. Trends Pharmacol Sci 1992;13:61-9.
5. Civelli O, Bunzow JR, Grandy DK. Molecular diversity of the dopamine receptors. Annu Rev Pharmacol Toxicol 1993;33:281-307.
6. Sokoloff P, Schwartz JC. Novel dopamine receptors half a decade later. Trends Pharmacol Sci 1995;16:270-5.
7. Missale C, Nash SR, Robinson SW, et al. Dopamine receptors: from structure to function. Physiol Rev 1998;78:189-225.
8. Carlsson A. A paradigm shift in brain research. Science 2001;294:1021-4.
9. Mustard JA, Beggs KT, Mercer AR. Molecular biology of the invertebrate dopamine receptors. Arch Insect Biochem Physiol 2005;59:103-17.
10. Guiramand J, Montmayeur JP, Ceraline J, et al. Alternative splicing of the dopamine D2 receptor directs specificity of coupling to G-proteins. J Biol Chem 1995;270:7354-7358.
11. Centonze D, Gubellini P, Usiello A, et al. Differential contribution of dopamine D2S and D2L receptors in the modulation of glutamate and GABA transmission in the striatum. Neuroscience 2004;129:157-66.
12. Lindgren N, Usiello A, Goiny M, et al. Distinct roles of dopamine D2L and D2S receptor isoforms in the regulation of protein phosphorylation at presynaptic and postsynaptic sites. Proc Natl Acad Sci USA 2003;100:4305-9.
13. Radl D, De Mei C, Chen E, et al. Each individual isoform of the dopamine D2 receptor protects from lactotroph hyperplasia. Mol Endocrinol 2013;27:953-65.
14. Millan MJ, Maiofiss L, Cussac D, et al. Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J Pharmacol Exp Ther 2002;303:791-804.
15. Perachon S, Schwartz JC, Sokoloff P. Functional potencies of new antiparkinsonian drugs at recombinant human dopamine D1, D2 and D3 receptors. Eur J Pharmacol 1999;366:293-300.
16. Santini E, Valjent E, Usiello A, et al. Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia. J Neurosci 2007;27:6995-7005.
17. Subramaniam S, Napolitano F, Mealer RG, et al. Rhes, a striatal-enriched small G protein, mediates mTOR signaling and L-DOPA-induced dyskinesia. Nat Neurosci 2012;15:191-3.
18. Fiorentini C, Savoia P, Savoldi D, et al. Persistent activation of the D1R/Shp-2/Erk1/2 pathway in l-DOPA-induced dyskinesia in the 6-hydroxy-dopamine rat model of Parkinson's disease. Neurobiol Dis 2013;54:339-48.
19. Westin JE, Vercammen L, Strome EM, et al. Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of L-DOPA-induced dyskinesia and the role of dopamine D1 receptors. Biol Psychiatry 2007;62:800-10.
20. George M, Amrutheshwar R, Rajkumar RP, et al. Newer antipsychotics and upcoming molecules for schizophrenia. Eur J Clin Pharmacol 2013;69:1497-509.
21. Beaulieu JM, Espinoza S, Gainetdinov RR. Dopamine receptors - IUPHAR Review 13. Br J Pharmacol 2015;172:1-23.
22. Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 2011;63:182-217.
23. Svenningsson P, Nishi A, Fisone G, et al. DARPP-32: an integrator of neurotransmission. Annu Rev Pharmacol Toxicol 2004;44:269-96.
24. Girault JA. Signaling in striatal neurons: the phosphoproteins of reward, addiction, and dyskinesia. Prog Mol Biol Transl Sci 2012;106:33-62.
25. Valjent E, Bertran-Gonzalez J, Bowling H, et al. Haloperidol regulates the state of phosphorylation of ribosomal protein S6 via activation of PKA and phosphorylation of DARPP-32. Neuropsychopharmacology 2011;36:2561-70.
26. Bonito-Oliva A, Pallottino S, Bertran-Gonzalez J, et al. Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. Neuropharmacology 2013;72:197-203.
27. Santini E, Feyder M, Gangarossa G, et al. Dopamine- and cAMP-regulated phosphoprotein of 32-kDa (DARPP-32)-dependent activation of extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin complex 1 (mTORC1) signaling in experimental parkinsonism. J Biol Chem 2012;287:27806-12.
28. Fiorentini C, Mattanza C, Collo G, et al. The tyrosine phosphatase Shp-2 interacts with the dopamine D(1) receptor and triggers D(1) -mediated Erk signaling in striatal neurons. J Neurochem 2011;117:253-63.
29. Fasano S, Bezard E, D'Antoni A, et al. Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with L-dopa-induced dyskinesia. Proc Natl Acad Sci USA 2010;107:21824-9.
30. Kisilevsky AE, Mulligan SJ, Altier C, et al. D1 receptors physically interact with N-type calcium channels to regulate channel distribution and dendritic calcium entry. Neuron 2008;58:557-70.
31. Hazelwood LA, Free RB, Cabrera DM, et al. Reciprocal modulation of function between the D1 and D2 dopamine receptors and the Na+,K+-ATPase. J Biol Chem 2008;283:36441-53.
32. Blom H, Rönnlund D, Scott L, et al. Nearest neighbor analysis of dopamine D1 receptors and Na(+)-K(+)-ATPases in dendritic spines dissected by STED microscopy. Microsc Res Tech 2012;75:220-8.
33. Swift JL, Godin AG, Doré K, et al. Quantification of receptor tyrosine kinase transactivation through direct dimerization and surface density measurements in single cells. Proc Natl Acad Sci USA 2011;108:7016-21.
34. Yoon S, Baik JH. Dopamine D2 receptor-mediated epidermal growth factor receptor transactivation through a disintegrin and metalloprotease regulates dopaminergic neuron development via extracellular signal-related kinase activation. J Biol Chem 2013;288:28435-46.
35. Gill RS, Hsiung MS, Sum CS, et al. The dopamine D4 receptor activates intracellular platelet-derived growth factor receptor beta to stimulate ERK1/2. Cell Signal 2010;22:285-90.
36. Chi SS, Vetiska SM, Gill RS, et al. Transactivation of PDGFRbeta by dopamine D4 receptor does not require PDGFRbeta dimerization. Mol Brain 2010;3:22.
37. Iwakura Y, Nawa H, Sora I, et al. Dopamine D1 receptor-induced signaling through TrkB receptors in striatal neurons. J Biol Chem 2008;283:15799-806.
38. Wang C, Buck DC, Yang R, et al. Dopamine D2 receptor stimulation of mitogen-activated protein kinases mediated by cell type-dependent transactivation of receptor tyrosine kinases. J Neurochem 2005;93:899-909.
39. Oak JN, Lavine N, Van Tol HH. Dopamine D(4) and D(2L) Receptor Stimulation of the Mitogen-Activated Protein Kinase Pathway Is Dependent on trans-Activation of the Platelet-Derived Growth Factor Receptor. Mol Pharmacol 2001;60:92-103.
40. Hernandez-Lopez S, Tkatch T, Perez-Garci E, et al. D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLC[beta]1-IP3-calcineurin-signaling cascade. J Neurosci 2000;20:8987-95.
41. Collo G, Bono F, Cavalleri L, et al. Pre-synaptic dopamine D(3) receptor mediates cocaine-induced structural plasticity in mesencephalic dopaminergic neurons via ERK and Akt pathways. J Neurochem 2012;120:765-78.
42. Collo G, Bono F, Cavalleri L, et al. Nicotine-induced structural plasticity in mesencephalic dopaminergic neurons is mediated by dopamine D3 receptors and Akt-mTORC1 signaling. Mol Pharmacol 2013;83:1176-89.
43. Beaulieu JM, Sotnikova TD, Marion S, et al. An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 2005;122:261-73.
44. Beaulieu JM, Tirotta E, Sotnikova TD, et al. Regulation of Akt signaling by D2 and D3 dopamine receptors in vivo. J Neurosci 2007;27:881-5.
45. Luttrell LM, Roudabush FL, Choy EW, et al. Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc Natl Acad Sci USA 2001;98:2449-54.
46. Souza BR, Romano-Silva MA, Tropepe V. Dopamine D2 receptor activity modulates Akt signaling and alters GABAergic neuron development and motor behavior in zebrafish larvae. J Neurosci 2011;31:5512-25.
47. Emamian ES, Hall D, Birnbaum MJ, et al. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet 2004;36:131-7.
48. Beaulieu JM, Marion S, Rodriguiz RM, et al. A beta-arrestin 2 signaling complex mediates lithium action on behavior. Cell 2008;132:125-36.
49. Beaulieu JM, Sotnikova TD, Yao WD, et al. Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc Natl Acad Sci USA 2004;101:5099-104.
50. Urs NM, Snyder JC, Jacobsen JP, et al. Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action. Proc Natl Acad Sci USA 2012;109:20732-7.
51. O'Brien WT, Huang J, Buccafusca R, et al. Glycogen synthase kinase-3 is essential for β-arrestin-2 complex formation and lithium-sensitive behaviors in mice. J Clin Invest 2011;121:3756-62.
52. Pan JQ, Lewis MC, Ketterman JK, et al. AKT kinase activity is required for lithium to modulate mood-related behaviors in mice. Neuropsychopharmacology 2011;36:1397-411.
53. Masri B, Salahpour A, Didriksen M, et al. Antagonism of dopamine D2 receptor/beta-arrestin 2 interaction is a common property of clinically effective antipsychotics. Proc Natl Acad Sci USA 2008;105:13656-61.
54. Angers S, Salahpour A, Bouvier M. Dimerization: an emerging concept for G protein-coupled receptor ontogeny and function. Annu Rev Pharmacol Toxicol 2002;42:409-35.
55. Fuxe K, Marcellino D, Guidolin D, et al. Heterodimers and receptor mosaics of different types of G-protein-coupled receptors. Physiology (Bethesda) 2008;23:322-32.
56. Ferré S, Baler R, Bouvier M, et al. Building a new conceptual framework for receptor heteromers. Nat Chem Biol 2009;5:131-4.
57. Milligan G. G protein-coupled receptor hetero-dimerization: contribution to pharmacology and function. Br J Pharmacol 2009;158:5-14.
58. So CH, Varghese G, Curley KJ, et al. D1 and D2 dopamine receptors form heterooligomers and cointernalize after selective activation of either receptor. Mol Pharmacol 2005;68:568-78.
59. Hasbi A, Fan T, Alijaniaram M, et al. Calcium signaling cascade links dopamine D1-D2 receptor heteromer to striatal BDNF production and neuronal growth. Proc Natl Acad Sci USA 2009;106:21377-82.
60. Rashid AJ, So CH, Kong MM, et al. D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. Proc Natl Acad Sci USA 2007;104:654-9.
61. Perreault ML, Hasbi A, Alijaniaram M, et al. The dopamine D1-D2 receptor heteromer localizes in dynorphin/enkephalin neurons: increased high affinity state following amphetamine and in schizophrenia. J Biol Chem 2010;285:36625-34.
62. Chun LS, Free RB, Doyle TB, et al. D1-D2 dopamine receptor synergy promotes calcium signaling via multiple mechanisms. Mol Pharmacol 2013;84:190-200.
63. Frederick AL, Yano H, Trifilieff P, et al. Evidence against dopamine D1/D2 receptor heteromers. Mol Psychiatry 2015;20:1373-85.
64. Pei L, Li S, Wang M, et al. Uncoupling the dopamine D1-D2 receptor complex exerts antidepressant-like effects. Nat Med 2010;16:1393-5.
65. Marcellino D, Ferré S, Casadó V, et al. Identification of dopamine D1-D3 receptor heteromers. Indications for a role of synergistic D1-D3 receptor interactions in the striatum. J Biol Chem 2008;283:26016-25.
66. Fiorentini C, Busi C, Gorruso E, et al. Reciprocal regulation of dopamine D1 and D3 receptor function and trafficking by heterodimerization. Mol Pharmacol 2008;74:59-69.
67. Guitart X, Navarro G, Moreno E, et al. Functional selectivity of allosteric interactions within G protein-coupled receptor oligomers: the dopamine D1-D3 receptor heterotetramer. Mol Pharmacol 2014;86:417-29.
68. Scarselli M, Novi F, Schallmach E, et al. D2/D3 dopamine receptor heterodimers exhibit unique functional properties. J Biol Chem 2001;276:30308-14.
69. Pou C, Mannoury la Cour C, Stoddart LA, et al. Functional homomers and heteromers of dopamine D2L and D3 receptors co-exist at the cell surface. J Biol Chem 2012;287:8864-78.
70. Ginés S, Hillion J, Torvinen M, et al. Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes. Proc Natl Acad Sci USA 2000;97:8606-11.
71. Toda S, Alguacil LF, Kalivas PW. Repeated cocaine administration changes the function and subcellular distribution of adenosine A1 receptor in the rat nucleus accumbens. J Neurochem 2003;87:1478-84.
72. Lee FJ, Xue S, Pei L, et al. Dual regulation of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor. Cell 2002;111:219-30.
73. Fiorentini C, Gardoni F, Spano P, et al. Regulation of dopamine D1 receptor trafficking and desensitization by oligomerization with glutamate N-methyl-D-aspartate receptors. J Biol Chem 2003;278:20196-202.
74. Cahill E, Pascoli V, Trifilieff P, et al. D1R/GluN1 complexes in the striatum integrate dopamine and glutamate signalling to control synaptic plasticity and cocaine-induced responses. Mol Psychiatry 2014;19:1295-304.
75. Aperia A, Greengard P. Dopamine receptor response to NMDA stimulation. Am J Psychiatry 2006;163:1682.
76. Canals M, Marcellino D, Fanelli F, et al. Adenosine A2A-dopamine D2 receptor-receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Biol Chem 2003;278:46741-9.
77. Hillion J, Canals M, Torvinen M, et al. Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors. J Biol Chem 2002;277:18091-7.
78. Espinoza S, Masri B, Salahpour A, et al. BRET approaches to characterize dopamine and TAAR1 receptor pharmacology and signaling. Methods Mol Biol 2013;964:107-22.
79. Espinoza S, Salahpour A, Masri B, et al. Functional interaction between trace amine-associated receptor 1 and dopamine D2 receptor. Mol Pharmacol 2011;80:416-25.
80. Cabello N, Gandía J, Bertarelli DC, et al. Metabotropic glutamate type 5, dopamine D2 and adenosine A2a receptors form higher-order oligomers in living cells. J Neurochem 2009;109:1497-507.
81. Carriba P, Navarro G, Ciruela F, et al. Detection of heteromerization of more than two proteins by sequential BRET-FRET. Nat Methods 2008;5:727-33.
82. Allen JA, Yost JM, Setola V, et al. Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy. Proc Natl Acad Sci USA 2011;108:18488-93.

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