Review
Looking for the role of cannabinoid receptor heteromers in striatal function

https://doi.org/10.1016/j.neuropharm.2008.06.076Get rights and content

Abstract

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.

Section snippets

Striatal spine modules and their diversity

The minimal portion of one or more neurons and/or one or more glial cells that operates as an independent integrative unit has been termed a “local module” (Ferré et al., 2007a). Conceptually, local module allows a better understanding of the functional relevance of extrasynaptic receptors, which are activated by volume transmission. Furthermore, the concept of local module provides a rationale for the functional relevance of neurotransmitter receptor heteromers, which can integrate signals

Endocannabinoid neurotransmission in the striatal spine modules

Endocannabinoids are membrane-derived signaling lipids which stimulate GPCRs receptors that are targeted by Δ9-tetrahydrocannabinol (THC), the addictive principle of marijuana. Two major endocannabinoids, anandamide and 2-arachidonylglycerol (2-AG), have been discovered. Like classical neurotransmitters they are released from neurons following neuronal depolarization and Ca2+ influx into the cell. Unlike classical neurotransmitters, they are not stored in vesicles, but are produced “on demand”

Oligomerization of GPCR

Oligomerization of GPCRs is a phenomenon that is becoming broadly accepted. When it comes to homomerization, at least two molecules of GPCR seem to be needed to interact with one heterotrimeric G protein complex (Baneres and Parello, 2003, Liang et al., 2003, Herrick-Davis et al., 2005). Strong support for homodimerization also comes from morphological evidence obtained with atomic force microscopy for rhodopsin (Fotiadis et al., 2003), protein crystallography for metabotropic glutamate

Cannabinoid CB1–dopamine D2 receptor heteromers

CB1–D2 receptor heteromerization has been demonstrated in co-transfected cells by co-immunoprecipitation and Fluorescence Resonance Energy Transfer (FRET) techniques (Kearn et al., 2005, Marcellino et al., 2008). The CB1–D2 receptor heteromer provides a nice example of G protein switching in the heteromer. Thus, both CB1 and D2 receptors are usually coupled to Gi-o proteins and their individual activation in co-transfected cells or primary striatal neurons in culture leads to inhibition of

Cannabinoid CB1–adenosine A2A receptor heteromers

CB1–A2A receptor heteromerization has been demonstrated by Bioluminescence Resonance Energy Transfer (BRET) in co-transfected cells (Carriba et al., 2007). In a human neuroblastoma cell line, Gi-dependent CB1 receptor signaling (inhibition of adenylyl-cyclase activity) was found to be completely dependent on A2A receptor co-activation. Thus, A2A receptor blockade or incubation with adenosine deaminase counteracted the ability of a CB1 agonist to inhibit forskolin-induced cAMP accumulation (

Cannabinoid CB1–μ opioid receptor heteromers

Heteromerization of CB1 and μ receptors was recently demonstrated in co-transfected cells with BRET (Rios et al., 2006), but direct functional interactions between these receptors were demonstrated much earlier by investigators looking for endogenous targets of THC, well before the discovery of endocannabinoids and cannabinoid receptors. It was found that THC allosterically modulates the binding of μ and δ (but not κ) opioid receptor ligands in membrane preparations from rat brain (Vaysse

Concluding remarks

The introduction of the two concepts, “local module” and “receptor heteromer”, facilitates the understanding of the role of interactions between different neurotransmitters in the brain (Ferré et al., 2007a). Local module also provides the best framework for understanding the role of “volume transmission” (Zoli et al., 1999). In the local module, the overflow of synaptically released and non-synaptically (neuronal or glial in origin) released neurotransmitters can converge and activate

Acknowledgements

Supported by the National Institute on Drug Abuse (Intramural Research funds), National Institutes of Health, Department of Health and Human Services.

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      Further studies are also necessary to assess the involvement of the D2Rs spliced isoforms the D2R long isoform and the D2R short isoform which mostly predominate in the post-synaptic and in the presynaptic sites, respectively, and seem to be specifically altered in schizo-affective disorders [75]. It is also important to highlight the strict correlation we observed between the transcriptional regulation of Cnr1 and Drd2 genes, which are co-expressed in the same presynaptic terminals of different brain regions [76] and whose coactivation and formation of CB1 and D2 heterodimers [77] is important for the modulation of GABAergic neurotransmission in the globus pallidus [78]. Moreover, their heterodimerization has been further supported by behavioral and biochemical data [79].

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