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.

Oligomerization of GPCRs involved in endocrine regulation

“…Several diseases or pathogenic conditions are associated with the function of this receptor including autism and schizophrenia (Gimpl & Fahrenholz 2001). It was recently reported that OTR and vasopressin receptors form homo-and heterodimers in vitro and in vivo (Albizu et al 2010b). Negative cooperative binding of oxytocin at the OTR was observed in in vitro systems, which points to a functional significance of dimerization (Albizu et al 2006).…”

Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?

“…The scope of functional understanding of neuropeptide actions has been further extended by the discovery of direct receptor-receptor interactions suggesting heteromerization and mosaic formation between different subtypes and subfamilies of GPCRs as shown for opioid receptor subtypes [28] [29]. The boost in the characterization of 3D crystal structures since publication of the ß 2 -adrenergic receptor structure by Kobilka's group in 2007 [30] gave rise to new challenges to SPECT and PET methods and tracer development as valuable proofs of mathematical models of receptor-ligand interactions in vivo.…”

“…an α 2A adrenergic-MOR heteromer [28] [29] [35]- [37] guiding future research also to bivalent ligands which could give additional functional informations but also new therapeutic approaches.…”

G Protein-Coupled Receptor Heterocomplexes in Neuropsychiatric Disorders

“…As certain receptor subtypes, such as dopamine, serotonin, glutamate, and adenosine receptors, have been shown to form GPCR heteromers in vitro in tissue culture and in vivo in animal models, a better understanding of their structure, neuroanatomical location, and physiological function may represent a new target for the design of drugs for the treatment of neuropsychiatric disorders such as schizophrenia, depression, suicidal behavior, and drug abuse. 45–48 Here, we will review recent findings related to GPCR heteromers and their role in central nervous system (CNS) function.…”

“…117–119 Together with coimmunoprecipitation and FRET experiments, 46 the reduction of the affinity of dopamine D2 receptor agonists in the presence of cannabinoid CB1 receptor agonists point toward expression of these two receptors as a GPCR heteromer. 45 It has also been suggested that the antagonistic interactions between cannabinoid CB1 and dopamine D2 receptors as a GPCR heteromer may also involve the adenosine A2A receptor. 120–122 This is supported by the demonstration that adenosine A2A receptors directly interact with both dopamine D2 56 and cannabinoid CB1 115 receptors.…”