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  • Numerous studies focused on the mechanisms

    2020-07-31

    Numerous studies focused on the mechanisms underlying allosteric changes induced receptor heteromerization and associated modification of downstream signaling but only few reports described roles of endogenous heteromers in vivo (Table 1). This is likely due to limitations of current approaches to detect heteromers in situ. In fact, class C GPCRs form stable oligomers but class A GPCRs oligomerization seems highly dynamic, and its existence is still a Cidofovir receptor of debate. Furthermore, most discoveries on receptor oligomers originate from studies in heterologous systems lacking the dense synaptic macroproteic complexes where receptors have multiple and dynamic interactors. These interactions, sometimes involving overlapping sites, represent a major challenge to selectively alter heteromer formation without impacting on the component receptor\'s interaction with other partners. This implies a thorough characterization of potential off-target effects and caution when interpreting the results. Such strategy design could benefit from crystal structures of the receptors to model the interface of heteromers, as recently performed for D2R/A2R (Borroto-Escuela et al., 2018c). This could facilitate the identification of the minimal amino-acid residues necessary for receptor heteromerization, the design of non-peptidic interfering molecules or bi-valent compounds selectively targeting receptor oligomers (Soriano et al., 2009). Several DA receptors heteromers with a therapeutic potential have been described, including D1R/D3R (Fiorentini et al., 2010), but their roles remain to be established. Moreover, most studies on receptor heteromers in addiction focused on the striatum because of its key role in the pathology and its enrichment in DA receptors. However, a thorough characterization of heteromer expression within the entire brain reward circuit would be of importance considering the implication of various brain regions in distinct components of addiction. Moreover, the implication of DA receptor heteromers has been mainly studied in the initial phases of drug exposure. Addressing their roles in each phases of drug addiction (maintenance, craving and relapse) seems of crucial importance as it could open new routes for the development of selective strategies targeting these heteromers for the treatment of drug addiction.
    Declaration of interest
    Acknowledgements The work from PV\'s group was supported by Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université, Agence Nationale pour la Recherche (ANR-15-CE16-0017), Fondation Jérôme Lejeune, Fondation pour la Recherche Médicale (FRM), the Bio-Psy labex cluster of excellence and the Ecole des Neurosciences de Paris (ENP). AA is the recipient of PhD fellowship from the French ministry of research. PT was supported by Institut National de la Recherche Agronomique (INRA, University of Bordeaux, Région Aquitaine, ANR “SynLip” (ANR-16-CE16-0022), Idex Bordeaux “chaire d\'installation” (ANR-10-IDEX-03-02) and NARSAD Young Investigator Grant from the Brain and Behavior Foundation. RW is the recipient of PhD fellowship from the French ministry of research.