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


METHODS
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.


CONCLUSIONS
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.
University of Padova, Department of Molecular Medicine , via Gabelli 65, 35121 Padova , Italy +39 049 8272316 ; +39 049 8272319 ; diego.guidolin@unipd.it.
Diego
D
Guidolin
Luigi F
LF
Agnati
Manuela
M
Marcoli
Dasiel O
DO
Borroto-Escuela
Kjell
K
Fuxe
D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D058990:Molecular Targeted Therapy; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000071557:beta-Arrestins
D019390:Arrestins; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins
G protein-coupled receptors; allosteric modulation; heteromers; neurology; neuropsychopharmacology; receptor-receptor interactions