Receptor heteromerization in adenosine A _2A receptor signaling

Abstract

Recently evidence has been presented that adenosine A2A and dopamine D2 receptors form functional heteromeric receptor complexes as demonstrated in human neuroblastoma cells and mouse fibroblast Ltk- cells. These A2A/D2 heteromeric receptor complexes undergo coaggregation, cointernalization, and codesensitization on D2 or A2A receptor agonist treatments and especially after combined agonist treatment. It is hypothesized that the A2A/D2 receptor heteromer represents the molecular basis for the antagonistic A2A/D2 receptor interactions demonstrated at the biochemical and behavioral levels. Functional heteromeric complexes between A2A and metabotropic glutamate 5 receptors (mGluR5) have also recently been demonstrated in HEK-293 cells and rat striatal membrane preparations. The A2A/mGluR5 receptor heteromer may account for the synergism found after combined agonist treatments demonstrated in different in vitro and in vivo models. D2, A2A, and mGluR5 receptors are found together in the dendritic spines of the striatopallidal GABA neurons. Therefore, possible D2/A2A/mGluR5 multimeric receptor complexes and the receptor interactions within them may have a major role in controlling the dorsal and ventral striatopallidal GABA neurons involved in Parkinson's disease and in schizophrenia and drug addiction, respectively.

Allosteric Modulation of Dopamine D2 Receptors by Homocysteine

“…[33][34][35] The present study is based on the previous demonstration of the existence of A 2A-D2 receptor heteromers and of their importance for the optimal treatment of Parkinsonian patients. [36][37][38] In this context, the results obtained can be of paramount importance. In fact, the present study demonstrates that homocysteine acts as an allosteric D 2 receptor antagonist, by selectively reducing the affinity of D2 receptors for agonists but not for antagonists.…”

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

“…A 1 and A 2A receptors are expressed in the brain, with A 2A being primarily localized to the dorsal striatum, nucleus accumbens, olfactory tubercle, and external globus pallidus (GPe) (Schwarzschild et al, 2006). In the striatum, A 2A receptors are co-localized with dopamine D 2 receptors, the peptide enkephalin, and the metabotropic glutamate receptor 5 (mGluR5), with which they functionally interact in dendrites and spines of medium spiny striatopallidal neurons within the indirect pathway of the basal ganglia (Fuxe et al, 2003(Fuxe et al, , 2007a(Fuxe et al, , b, 2010aTanganelli et al, 2004;Kachroo et al, 2005;Simola et al, 2008;Agnati et al, 2010;Tozzi et al, 2011) (Figure 1). D 2 and A 2A receptors have opposite effects on the activity of striatal neurons (Ferré et al, 1997).…”

Association between ADORA2A and DRD2 Polymorphisms and Caffeine-Induced Anxiety

“…Further, the minor allele of the DRD2 rs1110976 Intron 6 polymorphism, which was associated with low anxiety in this study, has previously been linked to reduced striatal density of DRD 2 receptors (Ritchie and Noble, 2003). Adenosine A 2A and dopamine DRD 2 receptors interact together in a reciprocally antagonistic manner (Fuxe et al, 2003;Torvinen et al, 2004). Caffeine, by antagonizing the action of adenosine at A 2A receptors, acts indirectly to potentiate dopaminergic transmission.…”

“…Second, there is reciprocal antagonism at the second messenger level reducing G-protein coupling and signaling. Activation of the A 2A receptor stimulates adenylyl cyclase activity whereas activation of DRD 2 inhibits adenylyl cyclase activity (Fuxe et al, 2003). Thus activation of A 2A uncouples DRD 2 from its G protein and reduces DRD 2 signaling.…”