Dopamine D2 and adenosine A2A receptors regulate NMDA-mediated excitation in accumbens neurons through A2A-D 2 receptor heteromerization

Bursting activity of striatal medium spiny neurons results from membrane potential oscillations between a down- and an upstate that could be regulated by G-protein-coupled receptors. Among these, dopamine D₂ and adenosine A_2A receptors are highly enriched in striatal neurons and exhibit strong interactions whose physiological significance and molecular mechanisms remain partially unclear. More particularly, respective involvements of common intracellular signaling cascades and A_2A-D₂ receptor heteromerization remain unknown. Here we show, by performing perforated-patch-clamp recordings on brain slices and loading competitive peptides, that D₂ and A_2A receptors regulate the induction by N-methyl-D-aspartate of a depolarized membrane potential plateau through mechanisms relying upon specific protein-protein interactions. Indeed, D ₂ receptor activation abolished transitions between a hyperpolarized resting potential and a depolarized plateau potential by regulating the Ca _V1.3a calcium channel activity through interactions with scaffold proteins Shank1/3. Noticeably, A_2A receptor activation had no effect per se but fully reversed the effects of D₂ receptor activation through a mechanism in which A_2A-D₂ receptors heteromerization is strictly mandatory, demonstrating therefore a first direct physiological relevance of these heteromers. Our results show that membrane potential transitions and firing patterns in striatal neurons are tightly controlled by D₂ and A_2A receptors through specific protein-protein interactions including A_2A-D₂ receptors heteromerization.