Adenosine A_2A and dopamine D₂ heteromeric receptor complexes and their function

The existence of A_2A-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 A_2A and D₂ receptors also coimmunoprecipitate in striatal tissue, giving evidence for the existence of A_2A-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 A_2A and D₂ agonists. The A_2A-D₂ heteromers could either be A _2A-D₂ heterodimers and/or higher-order A _2A-D₂ hetero-oligomers. In striatal neurons there are probably A_2A-D₂ heteromeric complexes, together with A_2A-D₂ homomeric complexes in the neuronal surface membrane. Their stoichiometry in various microdomains will have a major role in determining A_2A 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 I3 of the D₂ receptor are part of the A_2A-D₂ receptor interface, where electrostatic epitope-epitope interactions involving the N-terminal part of I3 of the D₂ receptor (arginine-rich epitope) play a major role, interacting with the carboxyl terminus of the A_2A receptor. Computerized modeling of A_2A-D₂ heteromers are in line with these findings. It seems likely that A_2A receptor-induced reduction of D₂ receptor recognition, G protein coupling, and signaling, as well as the existence of A_2A-D ₂ co-trafficking, are the consequence of the existence of an A _2A-D₂ receptor heteromer. The relevance of A _2A-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 A _2A-D₃ heteromeric receptor complexes in cotransfected cell lines has been summarized.