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 D 2 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–D 2 receptor heteromerization remain unknown. Here we show, by performing perforated-patch-clamp recordings on brain slices and loading competitive peptides, that D 2 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 V 1.3 a 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 D 2 receptor activation through a mechanism in which A 2A–D 2 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 D 2 and A 2A receptors through specific protein–protein interactions including A 2A–D 2 receptors heteromerization.