Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function
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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 EntriesAdenosine A2A receptors dopamine D2 receptors heteromers Parkinson’s disease schizophrenia
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- Agnati L. F., Ferré S., Lluis C., Franco R., and Fuxe K. (2003) Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among heptahelical receptors with examples from the striatopallidal GABA neurons. Pharmacol. Rev. 55, 509–550.PubMedCrossRefGoogle Scholar
- Canals M., Marcellino D., Fanelli F., Ciruela F., de Benedetti P., Goldberg S., et al. (2003) Adenosine A2A-dopamine D2 receptor-receptor heteromerization. Qualitative and quantitative assessment of fluorescence and bioluminescence energy transfer. J. Biol. Chem. 278, 46741–46749.PubMedCrossRefGoogle Scholar
- Ciruela F., Burgueno J., Casado V., Canals M., Marcelino D., Goldberg S. R., et al. (2004) Combining mass spectrometry and pull-down techniques for the study of receptor heteromerization. Direct epitope-epitope electrostatic interactions between adenosine A2A and dopamine D2 receptors. Anal. Chem. 76, 5354–5363.PubMedCrossRefGoogle Scholar
- Ferré S., Ciruela F., Woods A. S., Canals M., Burgueno J., Marcellino D., et al. (2003) Glutamate mGlu5-adenosine A2A-dopamine D2 receptor interactions in the striatum. Implications for drug therapy in neuropsychiatric disorders and drug abuse. Curr. Med. Chem. CNS Agents 33, 1–26.Google Scholar
- Fuxe K. and Agnati L. F. (1987) Receptor-Receptor Interactions. A New Intramembrane Integrative Mechanism. Macmillan Press, London, UK.Google Scholar
- Fuxe K., Ferré S., Zoli M., and Agnati L. F. (1998) Integrated events in central dopamine transmission as analyzed at multiple levels. Evidence for intra membrane adenosine A2A/dopamine D2 and adenosine A1/dopamine D1 receptor interactions in the basal ganglia. Brain Res. Rev. 26, 258–273.PubMedCrossRefGoogle Scholar
- Mellado M., Vila-Coro A. J., Martinez C., and Rodriguez-Frade J. M. (2002) Receptor dimerization: a key step in chemokine signaling. Cell. Mol. Biol. 47, 575–582.Google Scholar
- Svenningsson P., Lindskog M., Ledent C., Parmentier M., Greengard P., Fredholm B. B., and Fisone G. (2000) Regulation of the phosphorylation of the dopamineand cAMP-regulated phosphoprotein of 32 kDa in vivo by dopamine D1, dopamine D2, and adenosine A2A receptors. Proc. Natl. Acad. Sci. U. S. A. 97, 1856–1860.PubMedCrossRefGoogle Scholar