Adenosine A<SUB>2A</SUB> and Dopamine D<SUB>2</SUB> Heteromeric Receptor Complexes and Their Function

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 I3 of the D2 receptor are part of the A2A-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 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.

Dynamic Regulation of CXCR1 and CXCR2 Homo- and Heterodimers

“…Constant FRET 50 values for each receptor in homo-and heterodimeric complexes could indicate no difference in the functional state adopted by each receptor. By analogy to BRET parameters, however, we can also assume that if energy transfer reaches saturation and the curve is hyperbolic, FRET 50 would allow estimation of the apparent affinity between the partners involved (25,26,29). This concurs with the similar affinities reported for X1 and X2 homo-and heterodimers (12).…”

Receptor crosstalk: haloperidol treatment enhances A2A adenosine receptor functioning in a transfected cell model

“…In the corpus striatum and mesolimbic areas, where the two receptors mostly co-localise [20], it has been demonstrated that they are structurally associated to form functional heterodimers in which the adenosine and dopamine receptors mutually antagonise their respective responses [21][22][23][24][25]. On the basis of these results, A 2A AR agonists have been suggested as possible drugs, in association with antipsychotics, for the treatment of psychotic symptoms in schizophrenia and bipolar disorders [26,27].…”

Association between ADORA2A and DRD2 Polymorphisms and Caffeine-Induced Anxiety

“…Adenosine A 1 and A 2A receptors form functional heteromeric complexes with dopamine D 1 and D 2 receptors (DRD 1/2 , Fuxe et al, 2005) and there is evidence that these receptors interact at multiple levels to control cell function. First, the receptors physically interact and binding of adenosine to A 2A reduces affinity of DRD 2 for dopamine (Torvinen et al, 2004).…”