Disrupting GPCR Complexes with Smart Drug-like Peptides: History
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Subjects: Pharmacology & Pharmacy
Contributor:
David Andreu

G protein-coupled receptors (GPCRs) are a superfamily of proteins classically described as monomeric transmembrane (TM) receptors. However, increasing evidence indicates that many GPCRs form higher-order assemblies made up of monomers pertaining to identical (homo) or to various (hetero) receptors. The formation and structure of these oligomers, their physiological role and possible therapeutic applications raise a variety of issues that are currently being actively explored. In this context, synthetic peptides derived from TM domains stand out as powerful tools that can be predictably targeted to disrupt GPCR oligomers, especially at the interface level, eventually impairing their action.

  • peptide therapeutics
  • transmembrane peptides
  • GPCR oligomers
  • non-natural amino acids
  • cyclic peptides
  • retro-enantio

1. Introduction

G protein-coupled receptors (GPCRs) constitute the largest and most versatile superfamily of cell membrane-bound proteins, made up of seven trans-membrane α-helices (TM1 to TM7) [1][2][3] connected by intracellular (IL-1 to IL-3) and extracellular loops (EL-1 to EL-3), and coupled to an intracellular heterotrimeric G protein (e.g., Gs, Gi/o, Gq/11, G12/13) [4]. GPCRs are commonly grouped into six subfamilies (A-F) [5], based on sequence homology and functionality. Despite this apparent diversity, all GPCRs mediate their effects upon agonist-induced activation of the receptor at the extracellular site by a wide variety of ligands and then transduce the signal into intracellular responses [6]. Endogenous GPCR agonists are physically and chemically very diverse, including neurotransmitters (i.e., dopamine, serotonin), hormones (i.e., estrogen, angiotensin), proteins (i.e., chemokines), odors, photons, lipids (i.e., anandamide) or peptides (i.e., bradykinin), among many others [7]. Moreover, and more interestingly, ligand affinity for the GPCR primary (orthosteric) site and efficacy of activation can be increased or decreased by other effectors that bind to a separate (allosteric) site [8].
Given that GPCR signaling is involved in a diverse number of biological processes, GPCRs are considered ideal therapeutic targets [9] for a wide assortment of human diseases ranging from allergic rhinitis to pain, type-2 diabetes mellitus, obesity, depression, insomnia or cancer, to name just a few [10][11][12]; indeed, 34% of currently FDA-approved small-molecule drugs bind to GPCRs [13]. Originally described as cell-surface monomers that form a ternary complex with the extracellular ligand and the intracellular G protein [14], GPCR higher-order oligomers have in recent years been increasingly recognized as novel signaling units with functional properties distinct from their constituent receptors, thus opening up a new, only sparingly explored area of study within the GPCR field [15][16]. One possible strategy to probe into GPCR oligomerization and its impact on health conditions would consist in interfering in complex formation by means of exogenous synthetic peptides replicating TM domains involved in helix–helix interactions [17].

2. GPCR Oligomers

The human genome encodes nearly 1000 different GPCRs, each one highly specific to a signaling pathway [18]. However, growing evidence indicates that many GPCRs can form active higher-order oligomers constituted by equal (homo) or different (hetero) monomers [19][20][21][22][23][24][25][26], with functional properties distinct from their protomer components [27] and generally involved in both healthy and pathological processes [28], thus making them ideal targets for the development and screening of novel drugs [29][30].
One of the first reported GPCR oligomers involved δ- and κ-opioid receptors that, when co-expressed, formed a stable heterodimer with properties not found in cells expressing the same receptor monomers [31]. Subsequently, many other GPCR homo- and/or hetero-complexes have been unveiled, often displaying unique characteristics.
In many of these investigations the importance of TM helices in GPCR oligomerization has been demonstrated, portraying the GPCR complexes as dynamic species in which activation by the agonist induces a realignment of TM dimerization interfaces [32][33]. Indeed, it has been found that a dynamic equilibrium between monomeric and dimeric species can take place [34], modulated by ligand binding, which in turn can enhance or decrease heteromer interaction [35]. Therefore, while the minimal GPCR functional unit can be regarded as constituted by one monomeric receptor and one heterotrimeric G protein (1:1) [36], GPCR dimers can occur when: (i) two G proteins bind both dimer protomers (2:2) [37][38] or (ii) one G protein binds one protomer in the dimer (1:2) [39].
Another distinctive feature of some GPCRs is the switching of the G protein-coupled protomer when dimerization occurs. For instance, serotonin 5HT2AR couples Gq; however, heteromer formation by cannabinoid CB1R and 5HT2AR makes both receptors signal via Gi [40] (Figure 1A). In other words, some GPCR heteromers can couple G protein species different from those favoured by their protomers. Other reported examples are: (i) a heterodimer formed by dopamine D1 and D2 receptors that couples Gq instead of Gs or Gi [41] (Figure 1B); (ii) the heteromer formed by angiotensin AT1 and α2c-adrenergic receptors couples Gs instead of Gi or Gq [42]; and (iii) a melatonin MT1-MT2 receptor dimer that couples Gq instead of Gi [43].
/media/item_content/202202/62046a3f122capharmaceutics-14-00161-g001.png
Figure 1. (A) The serotonin 5HT2AR and the cannabinoid CB1R monomers couple Gi and Gq proteins, respectively; when dimerized, however, 5HT2AR switches Gq protein with Gi; (B) The dopamine D1R and D2R monomers couple Gs or Gi, respectively; however, the heterodimer D1R-D2R couples Gq; (C) The serotonin 5HT2AR antagonist blocks the signal activation of the cannabinoid CB1R agonist when dimerized.
Functionally, GPCR complexes can cause a positive or negative cooperation between promoters, i.e., ligand one binds to protomer one, enhancing or inhibiting, respectively, the affinity of ligand two for protomer two [44]. In general, intermolecular communication between GPCR homo- and heteromers tends to produce synergistic responses (i.e., functional cross-talk) [45]. A more singular phenomenon is cross-antagonism (Figure 1C), which occurs when a protomer antagonist blocks the signal activation of the other protomer [25][40][45]. Such a situation has been described for some GPCR complexes, including the metabotropic Gb1-Gb2 receptors [46], opioid δ-μ receptors [47], somatostatin SST5-dopamine D2 receptors [48], adenosine A2A-dopamine D1 receptors [49], orexin-corticotropin-releasing factor receptor [50] or angiotensin II AT1/dopamine D2 receptor [51].
Despite the extensive literature on GPCR oligomers, in most cases the assessment of their functionality has been only partially addressed and needs further investigation. In this context, chimeric peptide constructs have shown the ability to disrupt homo- and heteromer complexes, altering agonist-induced functionality and providing knowledge on the physiological role of GPCR receptor–receptor interactions [52][53][54][55].

3. Synthetic TM Peptides as Tools for GPCR Complex Exploration

The identification of protein–protein interaction interfaces constitutes a fundamental aspect in the study of GPCR complex formation [56], in that it can expand the understanding of the role that receptor oligomerization plays in intercellular communication or in some pathological conditions.
Increasing evidence indicates that specific TM helices are required for oligomerization, and that the synthetic peptides reproducing them are powerful tools to identify sequences essential for GPCR complexation and, by blocking their assembly, gain insights into the functional role of the complex [52][57][58].
For instance, Köfalvi et al. (2020) have recently studied how the adenosine-cannabinoid receptors, specifically the A2AR-CB1R heterotetramer interface, which also includes A2AR-A2AR and CB1R-CB1R homodimers, is established. To this end they have used computational modelling, with input from several biophysical and biochemical techniques, to design TM interference peptides reproducing each of the A2AR and CB1R TM1-7 helices. The synthetic versions, fused to the cell-penetrating HIV-Tat sequence, were tested by in vitro bimolecular fluorescence complementation (BiFC) experiments. Peptides replicating TM5 and TM6 of both receptors were able to disrupt the heterotetramer; thus, the involvement of their interfaces in the complex formation was confirmed. On the other hand, in the absence of the CB1R receptor, BiFC assays showed that the A2AR-A2AR homodimer was only disrupted by peptide A2AR TM6, while when A2AR was missing, CB1R TM4 was the only peptide disturbing CB1R-CB1R homodimer formation, altogether indicating that TM6 and TM4 sequences are involved in A2AR and CB1R homodimer interfaces, respectively [59].
Once the interfering peptides are identified, they can be used to investigate GPCR complex implications in numerous physiopathological disorders. As an example, Borroto-Escuela et al. (2018) found that rat A2AR TM5 peptide microinjection into the nucleus accumbens causes A2AR-D2R heteromer dissolution plus abrogation of the inhibitory effects of the A2AR agonist CGS21680 on cocaine self-administration, therefore confirming that the A2AR-D2R hetero-complex can be used as a novel target to treat cocaine disorders [53].
More examples where synthetic peptides replicating TM helices involved in dimerization have been shown to be able to split GPCR complex formations are included in Table 1. The in vitro (biophysical and/or biochemical) and in vivo assays used to confirm the existence of GPCR dimers in live cells and their implication (if known) in health disorders, are also presented.
Table 1. GPCR complexes disrupted by synthetic TM peptides.

GPCR Complex

TMs Involved in Dimerization

Synthetic TM

Disruptor Peptide

In Vitro/In Vivo

Assays Performed

Patho-Physiological Implication

Ref.

A2AR-D2R

TM4/5 interface

A2AR TM5

  • BRET

  • PLA

  • Cocaine self-administration

Cocaine use

[53]

APJR-OX1R

TM4/5 interface

APJ TM4, TM5

  • BRET

  • Co-IP

-

[60]

APJR homodimer

TM1, TM2, TM3, TM4

TM1, TM2, TM3, TM4

  • BRET

  • FRET

  • TIRFM

  • Co-IP

-

[61]

A2AR-CB1R

TM 5/6 interface

CB1R TM5 TM6

A2AR TM5 TM6

  • BiFC

  • BRET

  • CODA-RET

  • Glutamate release

Glutamate release

[59]

A1R-A2AR

TM 5/6 interface

A2AR TM4, TM5, TM6

A1R TM5 and TM6

  • BiFC

  • PLA

  • BRET

  • cAMP production

  • DMR

Neurodegeneration

Neuroinflammation

[62]

CB1R-5HT2AR

TM 5/6 interface

CB1R TM5, TM6

  • BRET

  • PLA

  • BiFC

  • NORT

  • Hot plate test

Cognitive impairment

[40]

M3R homodimer

TM1, TM5, TM7

TM1-TM5-TM7

  • BRET

-

[63]

CCKR homodimer

TM6

TM6

  • BRET

  • FRET

-

[64]

CCR5 homodimer

TM1, TM2, TM4

TM1, TM4

  • FRET Calcium determination

-

[65]

RhoR homodimer

TM1,TM2, TM4, TM5, H8

TM1, TM2, TM4, TM5

  • BRET

  • cAMP production

Phototransduction

[66]

β2AR homodimer

TM1, TM5, TM6, H8

TM6

  • Adenylyl cyclase activity

  • Densitometric analyses

-

[17]

SCTR

TM4

TM4

  • FRET

  • BRET

Liver diseases

[55]

AT1aR-SCTR

TM1/2 interface

TM4/4 interface

AT1aR TM1, TM4

SCTR TM2, TM4

  • BRET

  • FRET

  • cAMP

Hyperosmolality-induced drinking

[54]

FZD6 homodimer

TM4, TM5

TM4, TM5

  • FRAP

  • FCCS

Cancer and neurologic disorders

[67]

MOR-DOR

MOR TM1

MOR TM1

  • Co-IP

  • Immunoblotting

  • Tail immersion

Morphine tolerance

[68]

Abbreviations: 5HT2AR, serotonin receptor type 2 A; A1R, adenosine receptor type 1; A2AR, adenosine receptor type 2A; APJR, apelin receptor; AT1aR, angiotensin receptor type 1a; BiFC, bimolecular fluorescence complementation; BRET, bioluminescence resonance energy transfer; cAMP, cyclic adenosine monophosphate; CB1R, cannabinoid receptor type 1; CCKR, cholecystokinin receptor; CCR5, chemokine receptor type 5; CODA-RET, complemented donor-acceptor resonance energy transfer; Co-IP, co-immunoprecipitation; D2R, dopamine receptor type 2; DMR, dynamic mass redistribution; DOR, δ-opioid receptor; FCCS, fluorescence cross-correlation spectroscopy; FRAP, fluorescence recovery after photobleaching; FRET, fluorescence resonance energy transfer; FZD6R, Frizzled-6 receptor; M3R, muscarinic acetylcholine receptor type 3; MOR, μ-opioid receptors; NORT, novel object recognition test; OX1R, orexin receptor type 1; PLA, proximity ligation assay; RhoR, rhodopsin receptor; SCTR, secretin receptor; TIRF, total internal reflection fluorescence; β2AR, adrenergic receptor type β2.

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14010161

References

  1. Pierce, K.L.; Premont, R.T.; Lefkowitz, R.J. Seven-transmembrane receptors. Nat. Rev. Mol. Cell Biol. 2002, 3, 639–650.
  2. Lefkowitz, R.J. Historical review: A brief history and personal retrospective of seven-transmembrane receptors. Trends Pharmacol. Sci. 2004, 25, 413–422.
  3. Limbird, L.E.; Meyts, P.D.; Lefkowitz, R.J. Beta-adrenergic receptors: Evidence for negative cooperativity. Biochem. Biophys. Res. Commun. 1975, 64, 1160–1168.
  4. Wettschureck, N.; Offermanns, S. Mammalian G proteins and their cell type specific functions. Physiol. Rev. 2005, 85, 1159–1204.
  5. Attwood, T.K.; Findlay, J.B. Fingerprinting G-protein-coupled receptors. Protein Eng. 1994, 7, 195–203.
  6. Tuteja, N. Signaling through G protein coupled receptors. Plant Signal. Behav. 2009, 4, 942–947.
  7. Wacker, D.; Stevens, R.C.; Roth, B.L. How Ligands Illuminate GPCR Molecular Pharmacology. Cell 2017, 170, 414–427.
  8. Ferré, S.; Bonaventura, J.; Tomasi, D.; Navarro, G.; Moreno, E.; Cortés, A.; Lluís, C.; Casadó, V.; Volkow, N.D. Allosteric mechanisms within the adenosine A2A-dopamine D2 receptor heterotetramer. Neuropharmacology 2016, 104, 154–160.
  9. Cook, J.L. G protein-coupled receptors as disease targets: Emerging paradigms. Ochsner J. 2010, 10, 2–7.
  10. Sriram, K.; Insel, P.A. G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs? Mol. Pharmacol. 2018, 93, 251–258.
  11. Jacobson, K.A. New paradigms in GPCR drug discovery. Biochem. Pharmacol. 2015, 98, 541–555.
  12. Nieto Gutierrez, A.; McDonald, P.H. GPCRs: Emerging anti-cancer drug targets. Cell. Signal. 2018, 41, 65–74.
  13. Hauser, A.S.; Chavali, S.; Masuho, I.; Jahn, L.J.; Martemyanov, K.A.; Gloriam, D.E.; Babu, M.M. Pharmacogenomics of GPCR Drug Targets. Cell 2018, 172, 41–54.e19.
  14. Glukhova, A.; Draper-Joyce, C.J.; Sunahara, R.K.; Christopoulos, A.; Wootten, D.; Sexton, P.M. Rules of Engagement: GPCRs and G Proteins. ACS Pharmacol. Transl. Sci. 2018, 1, 73–83.
  15. Milligan, G.; Ward, R.J.; Marsango, S. GPCR homo-oligomerization. Curr. Opin. Cell Biol. 2019, 57, 40–47.
  16. Fuxe, K.; Borroto-Escuela, D.O.; Marcellino, D.; Romero-Fernandez, W.; Frankowska, M.; Guidolin, D.; Filip, M.; Ferraro, L.; Woods, A.S.; Tarakanov, A.; et al. GPCR heteromers and their allosteric receptor-receptor interactions. Curr. Med. Chem. 2012, 19, 356–363.
  17. Hebert, T.E.; Moffett, S.; Morello, J.P.; Loisel, T.P.; Bichet, D.G.; Barret, C.; Bouvier, M. A peptide derived from a beta2-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation. J. Biol. Chem. 1996, 271, 16384–16392.
  18. Fredriksson, R.; Lagerström, M.C.; Lundin, L.-G.; Schiöth, H.B. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol. Pharmacol. 2003, 63, 1256–1272.
  19. Li, X.; Zhou, M.; Huang, W.; Yang, H. N-glycosylation of the β(2) adrenergic receptor regulates receptor function by modulating dimerization. FEBS J. 2017, 284, 2004–2018.
  20. Bagher, A.M.; Young, A.P.; Laprairie, R.B.; Toguri, J.T.; Kelly, M.E.M.; Denovan-Wright, E.M. Heteromer formation between cannabinoid type 1 and dopamine type 2 receptors is altered by combination cannabinoid and antipsychotic treatments. J. Neurosci. Res. 2020, 98, 2496–2509.
  21. Ferré, S.; Ciruela, F. Functional and Neuroprotective Role of Striatal Adenosine A(2A) Receptor Heterotetramers. J. Caffeine Adenosine Res. 2019, 9, 89–97.
  22. Bono, F.; Mutti, V.; Fiorentini, C.; Missale, C. Dopamine D3 Receptor Heteromerization: Implications for Neuroplasticity and Neuroprotection. Biomolecules 2020, 10, 1016.
  23. Borroto-Escuela, D.O.; Tarakanov, A.O.; Brito, I.; Fuxe, K. Glutamate heteroreceptor complexes in the brain. Pharmacol. Rep. 2018, 70, 936–950.
  24. Bontempi, L.; Savoia, P.; Bono, F.; Fiorentini, C.; Missale, C. Dopamine D3 and acetylcholine nicotinic receptor heteromerization in midbrain dopamine neurons: Relevance for neuroplasticity. Eur. Neuropsychopharmacol. J. Eur. Coll. Neuropsychopharmacol. 2017, 27, 313–324.
  25. Guitart, X.; Navarro, G.; Moreno, E.; Yano, H.; Cai, N.-S.; Sánchez-Soto, M.; Kumar-Barodia, S.; Naidu, Y.T.; Mallol, J.; Cortés, A.; et al. Functional selectivity of allosteric interactions within G protein-coupled receptor oligomers: The dopamine D1-D3 receptor heterotetramer. Mol. Pharmacol. 2014, 86, 417–429.
  26. Cai, N.-S.; Quiroz, C.; Bonaventura, J.; Bonifazi, A.; Cole, T.O.; Purks, J.; Billing, A.S.; Massey, E.; Wagner, M.; Wish, E.D.; et al. Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids. J. Clin. Investig. 2019, 129, 2730–2744.
  27. Wang, J.; Hua, T.; Liu, Z.-J. Structural features of activated GPCR signaling complexes. Curr. Opin. Struct. Biol. 2020, 63, 82–89.
  28. Borroto-Escuela, D.O.; Ferraro, L.; Narvaez, M.; Tanganelli, S.; Beggiato, S.; Liu, F.; Rivera, A.; Fuxe, K. Multiple Adenosine-Dopamine (A2A-D2 Like) Heteroreceptor Complexes in the Brain and Their Role in Schizophrenia. Cells 2020, 9, 1077.
  29. Perreault, M.L.; Hasbi, A.; O’Dowd, B.F.; George, S.R. Heteromeric dopamine receptor signaling complexes: Emerging neurobiology and disease relevance. Neuropsychopharmacology 2014, 39, 156–168.
  30. Farran, B. An update on the physiological and therapeutic relevance of GPCR oligomers. Pharmacol. Res. 2017, 117, 303–327.
  31. Jordan, B.A.; Devi, L.A. G-protein-coupled receptor heterodimerization modulates receptor function. Nature 1999, 399, 697–700.
  32. Xue, L.; Sun, Q.; Zhao, H.; Rovira, X.; Gai, S.; He, Q.; Pin, J.-P.; Liu, J.; Rondard, P. Rearrangement of the transmembrane domain interfaces associated with the activation of a GPCR hetero-oligomer. Nat. Commun. 2019, 10, 2765.
  33. Kasai, R.S.; Ito, S.V.; Awane, R.M.; Fujiwara, T.K.; Kusumi, A. The Class-A GPCR Dopamine D2 Receptor Forms Transient Dimers Stabilized by Agonists: Detection by Single-Molecule Tracking. Cell Biochem. Biophys. 2018, 76, 29–37.
  34. Tabor, A.; Weisenburger, S.; Banerjee, A.; Purkayastha, N.; Kaindl, J.M.; Hübner, H.; Wei, L.; Grömer, T.W.; Kornhuber, J.; Tschammer, N.; et al. Visualization and ligand-induced modulation of dopamine receptor dimerization at the single molecule level. Sci. Rep. 2016, 6, 33233.
  35. Aslanoglou, D.; Alvarez-Curto, E.; Marsango, S.; Milligan, G. Distinct Agonist Regulation of Muscarinic Acetylcholine M2-M3 Heteromers and Their Corresponding Homomers. J. Biol. Chem. 2015, 290, 14785–14796.
  36. Gao, Y.; Westfield, G.; Erickson, J.W.; Cerione, R.A.; Skiniotis, G.; Ramachandran, S. Isolation and structure-function characterization of a signaling-active rhodopsin-G protein complex. J. Biol. Chem. 2017, 292, 14280–14289.
  37. Navarro, G.; Cordomi, A.; Zelman-Femiak, M.; Brugarolas, M.; Moreno, E.; Aguinaga, D.; Perez-Benito, L.; Cortes, A.; Casado, V.; Mallol, J.; et al. Quaternary structure of a G-protein-coupled receptor heterotetramer in complex with Gi and Gs. BMC Biol. 2016, 14, 26.
  38. Cordomí, A.; Navarro, G.; Aymerich, M.S.; Franco, R. Structures for G-Protein-Coupled Receptor Tetramers in Complex with G Proteins. Trends Biochem. Sci. 2015, 40, 548–551.
  39. Deganutti, G.; Salmaso, V.; Moro, S. Could Adenosine Recognize its Receptors with a Stoichiometry Other than 1:1? Mol. Inform. 2018, 37, e1800009.
  40. Vinals, X.; Moreno, E.; Lanfumey, L.; Cordomi, A.; Pastor, A.; de La Torre, R.; Gasperini, P.; Navarro, G.; Howell, L.A.; Pardo, L.; et al. Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors. PLoS Biol. 2015, 13, e1002194.
  41. Rashid, A.J.; So, C.H.; Kong, M.M.C.; Furtak, T.; El-Ghundi, M.; Cheng, R.; O’Dowd, B.F.; George, S.R. 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, 654–659.
  42. Bellot, M.; Galandrin, S.; Boularan, C.; Matthies, H.J.; Despas, F.; Denis, C.; Javitch, J.; Mazères, S.; Sanni, S.J.; Pons, V.; et al. Dual agonist occupancy of AT1-R-α2C-AR heterodimers results in atypical Gs-PKA signaling. Nat. Chem. Biol. 2015, 11, 271–279.
  43. Baba, K.; Benleulmi-Chaachoua, A.; Journé, A.-S.; Kamal, M.; Guillaume, J.-L.; Dussaud, S.; Gbahou, F.; Yettou, K.; Liu, C.; Contreras-Alcantara, S.; et al. Heteromeric MT1/MT2 melatonin receptors modulate photoreceptor function. Sci. Signal. 2013, 6, ra89.
  44. Smith, N.J.; Milligan, G. Allostery at G protein-coupled receptor homo- and heteromers: Uncharted pharmacological landscapes. Pharmacol. Rev. 2010, 62, 701–725.
  45. León-Navarro, D.A.; Albasanz, J.L.; Martín, M. Functional Cross-Talk between Adenosine and Metabotropic Glutamate Receptors. Curr. Neuropharmacol. 2019, 17, 422–437.
  46. Galvez, T.; Duthey, B.; Kniazeff, J.; Blahos, J.; Rovelli, G.; Bettler, B.; Prézeau, L.; Pin, J.P. Allosteric interactions between GB1 and GB2 subunits are required for optimal GABA(B) receptor function. EMBO J. 2001, 20, 2152–2159.
  47. Gomes, I.; Jordan, B.A.; Gupta, A.; Trapaidze, N.; Nagy, V.; Devi, L.A. Heterodimerization of mu and delta opioid receptors: A role in opiate synergy. J. Neurosci. 2000, 20, RC110.
  48. Rocheville, M.; Lange, D.C.; Kumar, U.; Patel, S.C.; Patel, R.C.; Patel, Y.C. Receptors for dopamine and somatostatin: Formation of hetero-oligomers with enhanced functional activity. Science 2000, 288, 154–157.
  49. Franco, R.; Ferre, S.; Agnati, L.; Torvinen, M.; Gines, S.; Hillion, J.; Casado, V.; Lledo, P.-M.; Zoli, M.; Lluis, C.; et al. Evidence for Adenosine/Dopamine Receptor Interactions: Indications for Heteromerization. Neuropsychopharmacology 2000, 23, S50–S59.
  50. Navarro, G.; Quiroz, C.; Moreno-Delgado, D.; Sierakowiak, A.; McDowell, K.; Moreno, E.; Rea, W.; Cai, N.-S.; Aguinaga, D.; Howell, L.A.; et al. Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine. J. Neurosci. 2015, 35, 6639–6653.
  51. Martínez-Pinilla, E.; Rodríguez-Pérez, A.I.; Navarro, G.; Aguinaga, D.; Moreno, E.; Lanciego, J.L.; Labandeira-García, J.L.; Franco, R. Dopamine D2 and angiotensin II type 1 receptors form functional heteromers in rat striatum. Biochem. Pharmacol. 2015, 96, 131–142.
  52. Young, B.M.; Nguyen, E.; Chedrawe, M.A.J.; Rainey, J.K.; Dupré, D.J. Differential Contribution of Transmembrane Domains IV, V, VI, and VII to Human Angiotensin II Type 1 Receptor Homomer Formation. J. Biol. Chem. 2017, 292, 3341–3350.
  53. Borroto-Escuela, D.O.; Wydra, K.; Li, X.; Rodriguez, D.; Carlsson, J.; Jastrzębska, J.; Filip, M.; Fuxe, K. Disruption of A2AR-D2R Heteroreceptor Complexes After A2AR Transmembrane 5 Peptide Administration Enhances Cocaine Self-Administration in Rats. Mol. Neurobiol. 2018, 55, 7038–7048.
  54. Lee, L.T.O.; Ng, S.Y.L.; Chu, J.Y.S.; Sekar, R.; Harikumar, K.G.; Miller, L.J.; Chow, B.K.C. Transmembrane peptides as unique tools to demonstrate the in vivo action of a cross-class GPCR heterocomplex. FASEB J. 2014, 28, 2632–2644.
  55. Harikumar, K.G.; Pinon, D.I.; Miller, L.J. Transmembrane segment IV contributes a functionally important interface for oligomerization of the Class II G protein-coupled secretin receptor. J. Biol. Chem. 2007, 282, 30363–30372.
  56. Guidolin, D.; Marcoli, M.; Tortorella, C.; Maura, G.; Agnati, L.F. Receptor-Receptor Interactions as a Widespread Phenomenon: Novel Targets for Drug Development? Front. Endocrinol. 2019, 10, 53.
  57. Møller, T.C.; Hottin, J.; Clerté, C.; Zwier, J.M.; Durroux, T.; Rondard, P.; Prézeau, L.; Royer, C.A.; Pin, J.-P.; Margeat, E.; et al. Oligomerization of a G protein-coupled receptor in neurons controlled by its structural dynamics. Sci. Rep. 2018, 8, 10414.
  58. Guidolin, D.; Marcoli, M.; Tortorella, C.; Maura, G.; Agnati, L.F. G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication. Rev. Neurosci. 2018, 29, 703–726.
  59. Köfalvi, A.; Moreno, E.; Cordomí, A.; Cai, N.-S.; Fernández-Dueñas, V.; Ferreira, S.G.; Guixà-González, R.; Sánchez-Soto, M.; Yano, H.; Casadó-Anguera, V.; et al. Control of glutamate release by complexes of adenosine and cannabinoid receptors. BMC Biol. 2020, 18, 9.
  60. Wan, L.; Xu, F.; Liu, C.; Ji, B.; Zhang, R.; Wang, P.; Wu, F.; Pan, Y.; Yang, C.; Wang, C.; et al. Transmembrane peptide 4 and 5 of APJ are essential for its heterodimerization with OX1R. Biochem. Biophys. Res. Commun. 2020, 521, 408–413.
  61. Cai, X.; Bai, B.; Zhang, R.; Wang, C.; Chen, J. Apelin receptor homodimer-oligomers revealed by single-molecule imaging and novel G protein-dependent signaling. Sci. Rep. 2017, 7, 40335.
  62. Navarro, G.; Cordomí, A.; Brugarolas, M.; Moreno, E.; Aguinaga, D.; Pérez-Benito, L.; Ferre, S.; Cortés, A.; Casadó, V.; Mallol, J.; et al. Cross-communication between Gi and Gs in a G-protein-coupled receptor heterotetramer guided by a receptor C-terminal domain. BMC Biol. 2018, 16, 24.
  63. McMillin, S.M.; Heusel, M.; Liu, T.; Costanzi, S.; Wess, J. Structural basis of M3 muscarinic receptor dimer/oligomer formation. J. Biol. Chem. 2011, 286, 28584–28598.
  64. Harikumar, K.G.; Dong, M.; Cheng, Z.; Pinon, D.I.; Lybrand, T.P.; Miller, L.J. Transmembrane Segment Peptides Can Disrupt Cholecystokinin Receptor Oligomerization without affecting Receptor Function. Biochemistry 2006, 45, 14706–14716.
  65. Hernanz-Falcón, P.; Rodríguez-Frade, J.M.; Serrano, A.; Juan, D.; del Sol, A.; Soriano, S.F.; Roncal, F.; Gómez, L.; Valencia, A.; Martínez-A, C.; et al. Identification of amino acid residues crucial for chemokine receptor dimerization. Nat. Immunol. 2004, 5, 216–223.
  66. Jastrzebska, B.; Chen, Y.; Orban, T.; Jin, H.; Hofmann, L.; Palczewski, K. Disruption of Rhodopsin Dimerization with Synthetic Peptides Targeting an Interaction Interface. J. Biol. Chem. 2015, 290, 25728–25744.
  67. Petersen, J.; Wright, S.C.; Rodríguez, D.; Matricon, P.; Lahav, N.; Vromen, A.; Friedler, A.; Strömqvist, J.; Wennmalm, S.; Carlsson, J.; et al. Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling. Nat. Commun. 2017, 8, 226.
  68. He, S.-Q.; Zhang, Z.-N.; Guan, J.-S.; Liu, H.-R.; Zhao, B.; Wang, H.-B.; Li, Q.; Yang, H.; Luo, J.; Li, Z.-Y.; et al. Facilitation of mu-opioid receptor activity by preventing delta-opioid receptor-mediated codegradation. Neuron 2011, 69, 120–131.
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