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  • Although the implication of DA and glutamate signaling cross

    2021-04-17

    Although the implication of DA and glutamate signaling crosstalk in drug-evoked neuronal adaptations is well acknowledged, targeting the cognate receptors to alleviate symptoms is associated with a loss of efficacy over time and the appearance of severe sides effects, likely due to the involvement of these receptors in fundamental physiological functions (Wang et al., 2012; Cahill et al., 2014a). Instead, a selective targeting of the molecular mechanisms responsible for the modulation of excitatory transmission by DA appears as a promising strategy. Beside local intracellular cascades downstream from DA receptors, a growing body of evidence supports that the physical interaction between receptors is a powerful mechanism by which receptors can mutually modify their functions through allosteric modulations. The formation of such receptor oligomers can engage two, or more, identical (homomers) or distinct (heteromers) receptors. These receptor complexes have been the subject of intense investigation because they can fine-tune downstream signaling and binding affinity of the component receptors in a spatio-temporal manner, which makes them attractive for the development of more selective pharmacological treatments for numerous neurological and psychiatric diseases (Missale et al., 2006, 2013; Borroto-Escuela et al., 2017a, 2017b). DA receptors have been shown – mostly in heterologous systems – to form many heteromers with other GPCR, ionotropic channels and transmembrane proteins, resulting in functional changes of partner receptors, modification of binding affinity for ligands and biased signaling. The diversity and biophysical properties of DA receptor heteromers have been exhaustively reviewed elsewhere (Wang et al., 2012; Ferré et al., 2016). Moreover, numerous studies showed the critical role of the physical interaction between DA receptors and NMDAR for their reciprocal modulation (Lee et al., 2002; Pei et al., 2004; Cepeda and Levine, 2006; Wang et al., 2012; Ladepeche et al., 2013), which makes them particularly relevant for drug addiction. The current review focuses on reports that were able to provide proof of concept that endogenous DA receptor heteromers in the Plerixafor can be modulated in response to exposure to drugs of abuse and eventually participate to drug-evoked neuronal adaptations (Table 1). For each DA receptor heteromer, we start from its historical discovery in heterologous systems, the identification of the protein-protein interaction domains and associated changes in signaling, to finally discuss their modulation in vivo and the strategies used to establish their potential roles in drug-evoked adaptations.
    D2R heteromers and addiction Notably because alterations of D2R-mediated signaling have been associated with numerous pathologies, there has been extensive work to identify putative heteromers formed by the D2R. Most of them were characterized in heterologous systems by bioluminescence or fluorescence resonance transfer (BRET/FRET) analyses, co-immunoprecipitation, or indirectly through modulation of ligand binding affinity and signaling effectors. These studies led to the identification of numerous and diverse receptors that are able to form complexes with the D2R and alter downstream signaling through allosteric modulations, as extensively reviewed (see Fuxe et al., 2014; Borroto-Escuela and Fuxe, 2017). Herein, we focus on D2R heteromers for which a functional impact has been characterized in vivo.
    D1R heteromers and addiction
    Conclusions and perspectives 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 matter 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).