Journal of Molecular Neuroscience

, Volume 26, Issue 2–3, pp 209–220 | Cite as

Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function

  • Kjell Fuxe
  • Sergi Ferré
  • Meritxell Canals
  • Maria Torvinen
  • Anton Terasmaa
  • Daniel Marcellino
  • Steven R. Goldberg
  • William Staines
  • Kirsten X. Jacobsen
  • Carmen Lluis
  • Amina s. Woods
  • Luigi F. Agnati
  • Rafael Franco
Review

Abstract

The existence of A2A-D2 heteromeric complexes is based on coimmunoprecipitation studies and on fluorescence resonance energy transfer and bioluminescence resonance energy transfer analyses. It has now become possible to show that A2A and D2 receptors also coimmunoprecipitate in striatal tissue, giving evidence for the existence of A2A-D2 heteromeric receptor complexes also in rat striatal tissue. The analysis gives evidence that these heteromers are constitutive, as they are observed in the absence of A2A and D2 agonists. The A2A-D2 heteromers could either be A2A-D2 heterodimers and/or higher-order A2A-D2 hetero-oligomers. In striatal neurons there are probably A2A-D2 heteromeric complexes, together with A2A-D2 homomeric complexes in the neuronal surface membrane. Their stoichiometry in various microdomains will have a major role in determining A2A and D2 signaling in the striatopallidal GABA neurons. Through the use of D2/D1 chimeras, evidence has been obtained that the fifth transmembrane (TM) domain and/or the 13 of the D2 receptor are part of the A2A-D2 receptor interface, where electrostatic epitope-epitope interactions involving the N-terminal part of 13 of the D2 receptor (arginine-rich epitope) play a major role, interacting with the carboxyl terminus of the A2A receptor. Computerized modeling of A2A-D2 heteromers are in line with these findings. It seems likely that A2A receptor-induced reduction of D2 receptor recognition, G protein coupling, and signaling, as well as the existence of A2A-D2 co-trafficking, are the consequence of the existence of an A2A-D2 receptor heteromer. The relevance of A2A-D2 heteromeric receptor complexes for Parkinson’s disease and schizophrenia is emphasized as well as for the treatment of these diseases. Finally, recent evidence for the existence of antagonistic A2A-D3 heteromeric receptor complexes in cotransfected cell lines has been summarized.

Index Entries

Adenosine A2A receptors dopamine D2 receptors heteromers Parkinson’s disease schizophrenia 

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Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  • Kjell Fuxe
    • 1
  • Sergi Ferré
    • 4
  • Meritxell Canals
    • 1
  • Maria Torvinen
    • 1
  • Anton Terasmaa
    • 1
  • Daniel Marcellino
    • 2
  • Steven R. Goldberg
    • 4
  • William Staines
    • 3
  • Kirsten X. Jacobsen
    • 3
  • Carmen Lluis
    • 2
  • Amina s. Woods
    • 4
  • Luigi F. Agnati
    • 5
  • Rafael Franco
    • 2
  1. 1.Department of Neuroscience, Division of Cellular and Molecular NeurochemistryKarolinska InstitutetStockholmSweden
  2. 2.Department of Biochemistry and Molecular BiologyUniversity of BarcelonaSpain
  3. 3.Cellular and Molecular MedicineUniversity of OttawaCanada
  4. 4.National Institute on Drug Abuse, DHHS, NIH, Intramural Research ProgramBaltimore
  5. 5.Department of Biomedical SciencesUniversity of Modena and Reggio EmiliaModenaItaly

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