Receptor, Ligand and Transducer Contributions to Dopamine D2 Receptor Functional Selectivity

PloS One
Sean PetersonMarc G Caron

Abstract

Functional selectivity (or biased agonism) is a property exhibited by some G protein-coupled receptor (GPCR) ligands, which results in the modulation of a subset of a receptor's signaling capabilities and more precise control over complex biological processes. The dopamine D2 receptor (D2R) exhibits pleiotropic responses to the biogenic amine dopamine (DA) to mediate complex central nervous system functions through activation of G proteins and β-arrestins. D2R is a prominent therapeutic target for psychological and neurological disorders in which DA biology is dysregulated and targeting D2R with functionally selective drugs could provide a means by which pharmacotherapies could be developed. However, factors that determine GPCR functional selectivity in vivo may be multiple with receptors, ligands and transducers contributing to the process. We have recently described a mutagenesis approach to engineer biased D2R mutants in which G protein-dependent ([Gprot]D2R) and β-arrestin-dependent signaling ([βarr]D2R) were successfully separated (Peterson, et al. PNAS, 2015). Here, permutations of these mutants were used to identify critical determinants of the D2R signaling complex that impart signaling bias in response to the natural o...Continue Reading

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Citations

May 11, 2017·Journal of Medicinal Chemistry·Barbara MännelPeter Gmeiner
Dec 3, 2016·Proceedings of the National Academy of Sciences of the United States of America·Nikhil M UrsMarc G Caron
Mar 1, 2018·The Journal of Biological Chemistry·Thomas F PackMarc G Caron
Jun 9, 2016·Korean journal of family medicine·Ather Muneer
Feb 19, 2019·ACS Pharmacology & Translational Science·Alessandro BonifaziAmy Hauck Newman
Apr 8, 2020·ACS Pharmacology & Translational Science·Krisztian TothLarry S Barak

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Methods Mentioned

BETA
dissection
BRET

Software Mentioned

BRET
Graphpad Prism

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