Heteromerization of G protein-coupled receptors: relevance to neurological disorders and neurotherapeutics

Abstract

Because G protein-coupled receptors (GPCRs) are numerous, widely expressed and involved in major physiological responses, they represent a relevant therapeutic target for drug discovery, particularly regarding pharmacological treatments of neurological disorders. Among the biological phenomena regulating receptor function, GPCR heteromerization is an important emerging area of interest and investigation. There is increasing evidence showing that heteromerization contributes to the pharmacological heterogeneity of GPCRs by modulating receptor ontogeny, activation and recycling. Although in many cases the physiological relevance of receptor heteromerization has not been fully established, the unique pharmacological and functional properties of heteromers are likely to lead to new strategies in clinical medicine. This review describes the main GPCR heteromers and their implications for major neurological disorders such as Parkinson's disease, schizophrenia and addiction. A better understanding of molecular mechanisms underlying drug interactions related to the targeting of receptor heteromers could provide more specific and efficient therapeutic agents for the treatment of brain diseases.

Fig. (1). Roles of GPCR heteromerization

(a) Heteromerization is first involved on maturation, folding and receptor expression at the cell surface by modulating its targeting from the endoplasmic reticulum or internalization. (b) At the plasma membrane, GPCR heteromerization can induce positive (+) or negative (−) cooperative ligand binding leading to specific pharmacological profiles. (c) Heteromerization can have a functional role by promoting or attenuating the specific G-protein coupling of a single receptor constituting the heteromer. In some cases, this regulation can open to a new signaling pathway (to a new G protein coupling or to a switch to other signaling protein recruitment like β-arrestin recruitment). (R1: receptor 1, R2: receptor 2, L1: ligand 1, L2: ligand 2, G1: G protein 1, G2: G protein 2, G3: G protein 3, ER: endoplasmic reticulum)

Fig. (2). Functional crosstalk between glutamate mGluR2 and serotonin 5-HT_2AR resulting of their heteromerization

(a) The physical interaction between the serotonin 5-HT_2AR and glutamate mGluR2 belonging to the GPCR classes 1 and 3, respectively, is mediated by mGluR2 tramsmembrane domains 4 (TM4) and 5 (TM5). (b) 5-HT_2AR hallucinogen agonist (DOI / DOM / DOB) affinities are higher in the presence of the mGluR2 agonist (LY379268) which induces a positive cooperative binding within the heteromer (1 and 2). By contrast, mGluR2 agonist (LY379268 / DCG-IV / L-CCG-I) affinities are lower in the presence of the 5-HT_2AR agonist (DOI) which induces a negative cooperative binding within the heteromer (3 and 4). (c) While 5-HT_2AR and mGluR2 are mainly coupled to the G_q/11 and G_i/o proteins, respectively, hallucinogen (DOI)-stimulated mGluR2-5-HT_2AR heteromer enhances significantly the G_i/o protein coupling (1). This effect is reversed in the presence of the mGluR2 agonist (LY379268) which enhances the G_q/11 protein coupling (2) suggesting a putative role of this compound as an antipsychotic drug able to abolish specific hallucinogen-induced effects. See [136].

Fig. (3). GPCR heteromer-specific drug targets

(a) Specific targeting of a GPCR only involved in a heteromeric formation. Regarding receptor heteromers involved in neurological diseases, antiparkinsonian SKF83959 [178] and antipsychotic l-stepholidine [179] are specific for D₁R-D₂R heteromer while antiparkinsonians S32504, ropinirole and pramipexole are specific for D₂R-D₃R heteromer [59]. (b) Bivalent ligands modulate specifically heteromers by binding both GPCRs. The adenosine A_2AR antagonist – dopamine D₂R agonist bivalent ligand specific for the A_2AR-D₂R heteromer could be used as a potent antiparkinsonian agent [182].