Dopamine receptors: Introduction

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. » Email us

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 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 [45,70]. 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 [45,70]. 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 [12] 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 [20,53,66,68] and [16]). 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 [54]. 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 [20,66,68] [53] and [16]). 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 [20,66,68] and [53]) and display specific functional and signaling properties [18,38,48,61]. Splice variants of the D3 receptor and polymorphic variants of the D4 receptor have also been identified (reviewed in [68] and [53].

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 [52,58]. 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 [31,64,71,78]; 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-HT2A, and have a lower incidence of side effects, still possess antagonistic activity at D2 receptors [34] (and reviewed in [4]).

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 [4]).

The classical view of dopamine receptor signaling implies that the D1 receptor stimulates the cAMP/PKA/DARPP-32 pathway [5,37,72] while the D2 and, to a lesser extent, the D3 receptors inhibit this pathway (reviewed in [53]). 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 [11,63-64,76]. 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 [30-31] and DARPP-32-mediated inhibition of protein phosphatase-1 [63]. 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 [26,31,64,71]. 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 [46] (and reviewed in [4]) and that the D1 and D2 receptors modulate the Na+-K+ ATPase [10,41]. Moreover, both D1-like and D2-like receptors transactivate tyrosine kinase receptors [35,73,79][44,56,77]. 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 [5,21-22,42].

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 [4-5,7,9]. 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 [4-5,7,9,49]). 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 ([4-5,7,9,23,69]. 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 [6,8,55,57,75] and that all antipsychotics prevent agonist-induced arrestin 2/3 (β-arrestin) recruitment to the D2 receptor [51].

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 [2,27,33]). 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 [19,32,40,59,62,67], D1 and D3 receptors [28,39,50], D2 and D3 receptors [60,65], D1 and adenosine A1 receptors [36,74], D1 and glutamate NMDA receptors [3,14,29,47], D2 and adenosine A2A receptors [15,43], D2 and trace amine TAAR1 [24-25] have been identified and characterized in the last ten years. High order heteromers such as D2/mGluR5/A2A receptors [13] and D2/A2A/CB1 [17] 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 [4]).

The recent discovery of D2 receptor signaling heterogeneity has led to a reconsideration of the mechanism(s) of action of some antipsychotics [75] 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 [51], 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 [1] (reviewed in [4]). 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

Show »

1. Allen JA, Yost JM, Setola V, Chen X, Sassano MF, Chen M, Peterson S, Yadav PN, Huang XP, Feng B et al.. (2011) Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy. Proc. Natl. Acad. Sci. U.S.A.108 (45): 18488-93. [PMID:22025698]

2. Angers S, Salahpour A, Bouvier M. (2002) Dimerization: an emerging concept for G protein-coupled receptor ontogeny and function. Annu. Rev. Pharmacol. Toxicol.42: 409-35. [PMID:11807178]

3. Aperia A, Greengard P. (2006) Dopamine receptor response to NMDA stimulation. Am J Psychiatry163 (10): 1682. [PMID:17012674]

4. Beaulieu JM, Espinoza S, Gainetdinov RR. (2015) Dopamine receptors - IUPHAR Review 13. Br. J. Pharmacol.172 (1): 1-23. [PMID:25671228]

5. Beaulieu JM, Gainetdinov RR. (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol. Rev.63 (1): 182-217. [PMID:21303898]

6. Beaulieu JM, Marion S, Rodriguiz RM, Medvedev IO, Sotnikova TD, Ghisi V, Wetsel WC, Lefkowitz RJ, Gainetdinov RR, Caron MG. (2008) A beta-arrestin 2 signaling complex mediates lithium action on behavior. Cell132 (1): 125-36. [PMID:18191226]

7. Beaulieu JM, Sotnikova TD, Marion S, Lefkowitz RJ, Gainetdinov RR, Caron MG. (2005) An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell122 (2): 261-73. [PMID:16051150]

8. Beaulieu JM, Sotnikova TD, Yao WD, Kockeritz L, Woodgett JR, Gainetdinov RR, Caron MG. (2004) Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc. Natl. Acad. Sci. U.S.A.101 (14): 5099-104. [PMID:15044694]

9. Beaulieu JM, Tirotta E, Sotnikova TD, Masri B, Salahpour A, Gainetdinov RR, Borrelli E, Caron MG. (2007) Regulation of Akt signaling by D2 and D3 dopamine receptors in vivo. J. Neurosci.27 (4): 881-5. [PMID:17251429]

10. Blom H, Rönnlund D, Scott L, Spicarova Z, Rantanen V, Widengren J, Aperia A, Brismar H. (2012) Nearest neighbor analysis of dopamine D1 receptors and Na(+)-K(+)-ATPases in dendritic spines dissected by STED microscopy. Microsc. Res. Tech.75 (2): 220-8. [PMID:21809413]

11. Bonito-Oliva A, Pallottino S, Bertran-Gonzalez J, Girault JA, Valjent E, Fisone G. (2013) Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. Neuropharmacology72: 197-203. [PMID:23643747]

12. Bunzow JR, Van Tol HH, Grandy DK, Albert P, Salon J, Christie M, Machida CA, Neve KA, Civelli O. (1988) Cloning and expression of a rat D2 dopamine receptor cDNA. Nature336: 783-787. [PMID:2974511]

13. Cabello N, Gandía J, Bertarelli DC, Watanabe M, Lluís C, Franco R, Ferré S, Luján R, Ciruela F. (2009) Metabotropic glutamate type 5, dopamine D2 and adenosine A2a receptors form higher-order oligomers in living cells. J. Neurochem.109 (5): 1497-507. [PMID:19344374]

14. Cahill E, Pascoli V, Trifilieff P, Savoldi D, Kappès V, Lüscher C, Caboche J, Vanhoutte P. (2014) D1R/GluN1 complexes in the striatum integrate dopamine and glutamate signalling to control synaptic plasticity and cocaine-induced responses. Mol. Psychiatry19 (12): 1295-304. [PMID:25070539]

15. Canals M, Marcellino D, Fanelli F, Ciruela F, de Benedetti P, Goldberg SR, Neve K, Fuxe K, Agnati LF, Woods AS et al.. (2003) Adenosine A2A-dopamine D2 receptor-receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J. Biol. Chem.278 (47): 46741-9. [PMID:12933819]

16. Carlsson A. (2001) A paradigm shift in brain research. Science294 (5544): 1021-4. [PMID:11691978]

17. Carriba P, Navarro G, Ciruela F, Ferré S, Casadó V, Agnati L, Cortés A, Mallol J, Fuxe K, Canela EI et al.. (2008) Detection of heteromerization of more than two proteins by sequential BRET-FRET. Nat. Methods5 (8): 727-33. [PMID:18587404]

18. Centonze D, Gubellini P, Usiello A, Rossi S, Tscherter A, Bracci E, Erbs E, Tognazzi N, Bernardi G, Pisani A et al.. (2004) Differential contribution of dopamine D2S and D2L receptors in the modulation of glutamate and GABA transmission in the striatum. Neuroscience129 (1): 157-66. [PMID:15489038]

19. Chun LS, Free RB, Doyle TB, Huang XP, Rankin ML, Sibley DR. (2013) D1-D2 dopamine receptor synergy promotes calcium signaling via multiple mechanisms. Mol. Pharmacol.84 (2): 190-200. [PMID:23680635]

20. Civelli O, Bunzow JR, Grandy DK. (1993) Molecular diversity of the dopamine receptors. Annu. Rev. Pharmacol. Toxicol.33: 281-307. [PMID:8494342]

21. Collo G, Bono F, Cavalleri L, Plebani L, Merlo Pich E, Millan MJ, Spano PF, Missale C. (2012) Pre-synaptic dopamine D(3) receptor mediates cocaine-induced structural plasticity in mesencephalic dopaminergic neurons via ERK and Akt pathways. J. Neurochem.120 (5): 765-78. [PMID:22145570]

22. Collo G, Bono F, Cavalleri L, Plebani L, Mitola S, Merlo Pich E, Millan MJ, Zoli M, Maskos U, Spano P et al.. (2013) Nicotine-induced structural plasticity in mesencephalic dopaminergic neurons is mediated by dopamine D3 receptors and Akt-mTORC1 signaling. Mol. Pharmacol.83 (6): 1176-89. [PMID:23543412]

23. Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA. (2004) Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat. Genet.36 (2): 131-7. [PMID:14745448]

24. Espinoza S, Masri B, Salahpour A, Gainetdinov RR. (2013) BRET approaches to characterize dopamine and TAAR1 receptor pharmacology and signaling. Methods Mol. Biol.964: 107-22. [PMID:23296781]

25. Espinoza S, Salahpour A, Masri B, Sotnikova TD, Messa M, Barak LS, Caron MG, Gainetdinov RR. (2011) Functional interaction between trace amine-associated receptor 1 and dopamine D2 receptor. Mol. Pharmacol.80 (3): 416-25. [PMID:21670104]

26. Fasano S, Bezard E, D'Antoni A, Francardo V, Indrigo M, Qin L, Doveró S, Cerovic M, Cenci MA, Brambilla R. (2010) 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. U.S.A.107 (50): 21824-9. [PMID:21115823]

27. Ferré S, Baler R, Bouvier M, Caron MG, Devi LA, Durroux T, Fuxe K, George SR, Javitch JA, Lohse MJ et al.. (2009) Building a new conceptual framework for receptor heteromers. Nat. Chem. Biol.5 (3): 131-4. [PMID:19219011]

28. Fiorentini C, Busi C, Gorruso E, Gotti C, Spano P, Missale C. (2008) Reciprocal regulation of dopamine D1 and D3 receptor function and trafficking by heterodimerization. Mol. Pharmacol.74 (1): 59-69. [PMID:18424554]

29. Fiorentini C, Gardoni F, Spano P, Di Luca M, Missale C. (2003) Regulation of dopamine D1 receptor trafficking and desensitization by oligomerization with glutamate N-methyl-D-aspartate receptors. J. Biol. Chem.278 (22): 20196-202. [PMID:12646556]

30. Fiorentini C, Mattanza C, Collo G, Savoia P, Spano P, Missale C. (2011) The tyrosine phosphatase Shp-2 interacts with the dopamine D(1) receptor and triggers D(1) -mediated Erk signaling in striatal neurons. J. Neurochem.117 (2): 253-63. [PMID:21272002]

31. Fiorentini C, Savoia P, Savoldi D, Barbon A, Missale C. (2013) 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.54: 339-48. [PMID:23328768]

32. Frederick AL, Yano H, Trifilieff P, Vishwasrao HD, Biezonski D, Mészáros J, Urizar E, Sibley DR, Kellendonk C, Sonntag KC et al.. (2015) Evidence against dopamine D1/D2 receptor heteromers. Mol. Psychiatry,  [Epub ahead of print]. [PMID:25560761]

33. Fuxe K, Marcellino D, Guidolin D, Woods AS, Agnati LF. (2008) Heterodimers and receptor mosaics of different types of G-protein-coupled receptors. Physiology (Bethesda)23: 322-32. [PMID:19074740]

34. George M, Amrutheshwar R, Rajkumar RP, Kattimani S, Dkhar SA. (2013) Newer antipsychotics and upcoming molecules for schizophrenia. Eur. J. Clin. Pharmacol.69 (8): 1497-509. [PMID:23545936]

35. Gill RS, Hsiung MS, Sum CS, Lavine N, Clark SD, Van Tol HH. (2010) The dopamine D4 receptor activates intracellular platelet-derived growth factor receptor beta to stimulate ERK1/2. Cell. Signal.22 (2): 285-90. [PMID:19782129]

36. Ginés S, Hillion J, Torvinen M, Le Crom S, Casadó V, Canela EI, Rondin S, Lew JY, Watson S, Zoli M et al.. (2000) Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes. Proc. Natl. Acad. Sci. U.S.A.97 (15): 8606-11. [PMID:10890919]

37. Girault JA. (2012) Signaling in striatal neurons: the phosphoproteins of reward, addiction, and dyskinesia. Prog Mol Biol Transl Sci106: 33-62. [PMID:22340713]

38. Guiramand J, Montmayeur JP, Ceraline J, Bhatia M, Borrelli E. (1995) Alternative splicing of the dopamine D2 receptor directs specificity of coupling to G-proteins. J Biol Chem270: 7354-7358. [PMID:7706278]

39. Guitart X, Navarro G, Moreno E, Yano H, Cai NS, Sánchez-Soto M, Kumar-Barodia S, Naidu YT, Mallol J, Cortés A et al.. (2014) Functional selectivity of allosteric interactions within G protein-coupled receptor oligomers: the dopamine D1-D3 receptor heterotetramer. Mol. Pharmacol.86 (4): 417-29. [PMID:25097189]

40. Hasbi A, Fan T, Alijaniaram M, Nguyen T, Perreault ML, O'Dowd BF, George SR. (2009) Calcium signaling cascade links dopamine D1-D2 receptor heteromer to striatal BDNF production and neuronal growth. Proc. Natl. Acad. Sci. U.S.A.106 (50): 21377-82. [PMID:19948956]

41. Hazelwood LA, Free RB, Cabrera DM, Skinbjerg M, Sibley DR. (2008) Reciprocal modulation of function between the D1 and D2 dopamine receptors and the Na+,K+-ATPase. J. Biol. Chem.283 (52): 36441-53. [PMID:18984584]

42. Hernandez-Lopez S, Tkatch T, Perez-Garci E, Galarraga E, Bargas J, Hamm H, Surmeier DJ. (2000) 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.20 (24): 8987-95. [PMID:11124974]

43. Hillion J, Canals M, Torvinen M, Casado V, Scott R, Terasmaa A, Hansson A, Watson S, Olah ME, Mallol J et al.. (2002) Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors. J. Biol. Chem.277 (20): 18091-7. [PMID:11872740]

44. Iwakura Y, Nawa H, Sora I, Chao MV. (2008) Dopamine D1 receptor-induced signaling through TrkB receptors in striatal neurons. J. Biol. Chem.283 (23): 15799-806. [PMID:18381284]

45. Kebabian JW, Calne DB. (1979) Multiple receptors for dopamine. Nature277: 93-96. [PMID:215920]

46. Kisilevsky AE, Mulligan SJ, Altier C, Iftinca MC, Varela D, Tai C, Chen L, Hameed S, Hamid J, Macvicar BA et al.. (2008) D1 receptors physically interact with N-type calcium channels to regulate channel distribution and dendritic calcium entry. Neuron58 (4): 557-70. [PMID:18498737]

47. Lee FJ, Xue S, Pei L, Vukusic B, Chéry N, Wang Y, Wang YT, Niznik HB, Yu XM, Liu F. (2002) Dual regulation of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor. Cell111 (2): 219-30. [PMID:12408866]

48. Lindgren N, Usiello A, Goiny M, Haycock J, Erbs E, Greengard P, Hokfelt T, Borrelli E, Fisone G. (2003) Distinct roles of dopamine D2L and D2S receptor isoforms in the regulation of protein phosphorylation at presynaptic and postsynaptic sites. Proc. Natl. Acad. Sci. U.S.A.100 (7): 4305-9. [PMID:12651945]

49. Luttrell LM, Roudabush FL, Choy EW, Miller WE, Field ME, Pierce KL, Lefkowitz RJ. (2001) Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc. Natl. Acad. Sci. U.S.A.98 (5): 2449-54. [PMID:11226259]

50. Marcellino D, Ferré S, Casadó V, Cortés A, Le Foll B, Mazzola C, Drago F, Saur O, Stark H, Soriano A et al.. (2008) Identification of dopamine D1-D3 receptor heteromers. Indications for a role of synergistic D1-D3 receptor interactions in the striatum. J. Biol. Chem.283 (38): 26016-25. [PMID:18644790]

51. Masri B, Salahpour A, Didriksen M, Ghisi V, Beaulieu JM, Gainetdinov RR, Caron MG. (2008) Antagonism of dopamine D2 receptor/beta-arrestin 2 interaction is a common property of clinically effective antipsychotics. Proc. Natl. Acad. Sci. U.S.A.105 (36): 13656-61. [PMID:18768802]

52. Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A. (2002) 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 Ther303: 791-804. [PMID:12388666]

53. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG. (1998) Dopamine receptors: from structure to function. Physiol. Rev.78 (1): 189-225. [PMID:9457173]

54. Mustard JA, Beggs KT, Mercer AR. (2005) Molecular biology of the invertebrate dopamine receptors. Arch Insect Biochem Physiol59: 103-117. [PMID:15986382]

55. O'Brien WT, Huang J, Buccafusca R, Garskof J, Valvezan AJ, Berry GT, Klein PS. (2011) Glycogen synthase kinase-3 is essential for β-arrestin-2 complex formation and lithium-sensitive behaviors in mice. J. Clin. Invest.121 (9): 3756-62. [PMID:21821916]

56. Oak JN, Lavine N, Van Tol HH. (2001) 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.60 (1): 92-103. [PMID:11408604]

57. Pan JQ, Lewis MC, Ketterman JK, Clore EL, Riley M, Richards KR, Berry-Scott E, Liu X, Wagner FF, Holson EB et al.. (2011) AKT kinase activity is required for lithium to modulate mood-related behaviors in mice. Neuropsychopharmacology36 (7): 1397-411. [PMID:21389981]

58. Perachon S, Schwartz JC, Sokoloff P. (1999) Functional potencies of new antiparkinsonian drugs at recombinant human dopamine D1, D2 and D3 receptors. Eur J Pharmacol366: 293-300. [PMID:10082211]

59. Perreault ML, Hasbi A, Alijaniaram M, Fan T, Varghese G, Fletcher PJ, Seeman P, O'Dowd BF, George SR. (2010) The dopamine D1-D2 receptor heteromer localizes in dynorphin/enkephalin neurons: increased high affinity state following amphetamine and in schizophrenia. J. Biol. Chem.285 (47): 36625-34. [PMID:20864528]

60. Pou C, Mannoury la Cour C, Stoddart LA, Millan MJ, Milligan G. (2012) Functional homomers and heteromers of dopamine D2L and D3 receptors co-exist at the cell surface. J. Biol. Chem.287 (12): 8864-78. [PMID:22291025]

61. Radl D, De Mei C, Chen E, Lee H, Borrelli E. (2013) Each individual isoform of the dopamine D2 receptor protects from lactotroph hyperplasia. Mol. Endocrinol.27 (6): 953-65. [PMID:23608643]

62. Rashid AJ, So CH, Kong MM, Furtak T, El-Ghundi M, Cheng R, O'Dowd BF, George SR. (2007) D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. Proc. Natl. Acad. Sci. U.S.A.104 (2): 654-9. [PMID:17194762]

63. Santini E, Feyder M, Gangarossa G, Bateup HS, Greengard P, Fisone G. (2012) 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.287 (33): 27806-12. [PMID:22753408]

64. Santini E, Valjent E, Usiello A, Carta M, Borgkvist A, Girault JA, Hervé D, Greengard P, Fisone G. (2007) Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia. J. Neurosci.27 (26): 6995-7005. [PMID:17596448]

65. Scarselli M, Novi F, Schallmach E, Lin R, Baragli A, Colzi A, Griffon N, Corsini GU, Sokoloff P, Levenson R et al.. (2001) D2/D3 dopamine receptor heterodimers exhibit unique functional properties. J. Biol. Chem.276 (32): 30308-14. [PMID:11373283]

66. Sibley DR, Monsma Jr FJ. (1992) Molecular biology of dopamine receptors. Trends Pharmacol. Sci.13 (2): 61-9. [PMID:1561715]

67. So CH, Varghese G, Curley KJ, Kong MM, Alijaniaram M, Ji X, Nguyen T, O'dowd BF, George SR. (2005) D1 and D2 dopamine receptors form heterooligomers and cointernalize after selective activation of either receptor. Mol. Pharmacol.68 (3): 568-78. [PMID:15923381]

68. Sokoloff P, Schwartz JC. (1995) Novel dopamine receptors half a decade later. Trends Pharmacol. Sci.16 (8): 270-5. [PMID:7482988]

69. Souza BR, Romano-Silva MA, Tropepe V. (2011) Dopamine D2 receptor activity modulates Akt signaling and alters GABAergic neuron development and motor behavior in zebrafish larvae. J. Neurosci.31 (14): 5512-25. [PMID:21471388]

70. Spano PF, Govoni S, Trabucchi M. (1978) Studies on the pharmacological properties of dopamine receptors in various areas of the central nervous system. Adv. Biochem. Psychopharmacol.19: 155-165. [PMID:358777]

71. Subramaniam S, Napolitano F, Mealer RG, Kim S, Errico F, Barrow R, Shahani N, Tyagi R, Snyder SH, Usiello A. (2012) Rhes, a striatal-enriched small G protein, mediates mTOR signaling and L-DOPA-induced dyskinesia. Nat. Neurosci.15 (2): 191-3. [PMID:22179112]

72. Svenningsson P, Nishi A, Fisone G, Girault JA, Nairn AC, Greengard P. (2004) DARPP-32: an integrator of neurotransmission. Annu. Rev. Pharmacol. Toxicol.44: 269-96. [PMID:14744247]

73. Swift JL, Godin AG, Doré K, Freland L, Bouchard N, Nimmo C, Sergeev M, De Koninck Y, Wiseman PW, Beaulieu JM. (2011) Quantification of receptor tyrosine kinase transactivation through direct dimerization and surface density measurements in single cells. Proc. Natl. Acad. Sci. U.S.A.108 (17): 7016-21. [PMID:21482778]

74. Toda S, Alguacil LF, Kalivas PW. (2003) Repeated cocaine administration changes the function and subcellular distribution of adenosine A1 receptor in the rat nucleus accumbens. J. Neurochem.87 (6): 1478-84. [PMID:14713303]

75. Urs NM, Snyder JC, Jacobsen JP, Peterson SM, Caron MG. (2012) Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action. Proc. Natl. Acad. Sci. U.S.A.109 (50): 20732-7. [PMID:23188793]

76. Valjent E, Bertran-Gonzalez J, Bowling H, Lopez S, Santini E, Matamales M, Bonito-Oliva A, Hervé D, Hoeffer C, Klann E et al.. (2011) Haloperidol regulates the state of phosphorylation of ribosomal protein S6 via activation of PKA and phosphorylation of DARPP-32. Neuropsychopharmacology36 (12): 2561-70. [PMID:21814187]

77. Wang C, Buck DC, Yang R, Macey TA, Neve KA. (2005) Dopamine D2 receptor stimulation of mitogen-activated protein kinases mediated by cell type-dependent transactivation of receptor tyrosine kinases. J. Neurochem.93 (4): 899-909. [PMID:15857393]

78. Westin JE, Vercammen L, Strome EM, Konradi C, Cenci MA. (2007) Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of L-DOPA-induced dyskinesia and the role of dopamine D1 receptors. Biol. Psychiatry62 (7): 800-10. [PMID:17662258]

79. Yoon S, Baik JH. (2013) 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.288 (40): 28435-46. [PMID:23955337]

How to cite this page

To cite this family introduction, please use the following:

Raul R. Gainetdinov, Jean-Martin Beaulieu, Emiliana Borrelli, Arvid Carlsson, Marc G. Caron, Stefano Espinoza, Gilberto Fisone, David K. Grandy, Maria Cristina Missale, Kim A. Neve, David R. Sibley, Pierre Sokoloff.
Dopamine receptors, introduction. Last modified on 09/03/2017. Accessed on 23/09/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=20.