G-protein-coupled receptor type A heteromers as an emerging therapeutic target

Abstract

Introduction: The discovery of receptor–receptor interactions (RRIs) in the early 1980s provided evidence that G-protein-coupled receptors (GPCRs) operate not only as monomers but also as heteromers, in which integration of the incoming signals takes place already at the plasma membrane level through allosteric RRIs. These integrative mechanisms give sophisticated dynamics to the structure and function of these receptor assemblies in terms of modulation of recognition, G-protein signaling and selectivity and switching to β-arrestin signaling.

Areas covered: The present review briefly describes the concept of direct RRI and the available data on the mechanisms of oligomer formation. Further, pharmacological data concerning the best characterized heteromers involving type A GPCRs will be analyzed to evaluate their profile as possible targets for the treatment of various diseases, in particular of impacting diseases of the CNS.

Expert opinion: GPCR heteromers have the potential to open a completely new field for pharmacology with likely a major impact in molecular medicine. Novel pharmacological strategies for the treatment of several pathologies have already been proposed. However, several challenges still exist to accurately characterize the role of the identified heteroreceptor complexes in pathology and to develop heteromer-specific ligands capable of efficiently exploiting their pharmacological features.

Keywords:

• allosteric modulation
• G protein-coupled receptors
• heteromers
• neurology
• neuropsychopharmacology
• receptor-receptor interactions

Declaration of interest

The authors are supported by a grant from University of Padova (ex-60%) and by the Swedish Medical Research Council (62X-00715-50-3) and AFA Forsakring (130328). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

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