Looking for the role of cannabinoid receptor heteromers in striatal function

The introduction of two concepts, “local module” and “receptor heteromer”, facilitates the understanding of the role of interactions between different neurotransmitters in the brain. In artificial cell systems, cannabinoid CB1 receptors form receptor heteromers with dopamine D2, adenosine A2A and μ opioid receptors. There is indirect but compelling evidence for the existence of the same CB1 receptor heteromers in striatal local modules centered in the dendritic spines of striatal GABAergic efferent neurons, particularly at a postsynaptic location. Their analysis provides new clues for the role of endocannabinoids in striatal function, which cannot only be considered as retrograde signals that inhibit neurotransmitter release. Recent studies using a new method to detect heteromerization of more than two proteins, which consists of sequential BRET–FRET (SRET) analysis, has demonstrated that CB1, D2 and A2A receptors can form heterotrimers in transfected cells. It is likely that functional CB1–A2A–D2 receptor heteromers can be found where they are highly co-expressed, in the dendritic spines of GABAergic enkephalinergic neurons. The functional properties of these multiple receptor heteromers and their role in striatal function need to be determined.