The various actions of dopamine (DA) on target neurons are mediated via prototypical 7-transmembrane G protein-coupled receptors (GPCR) that couple to various effectors through G protein-dependent mechanisms. However, it is now widely appreciated that GPCRs can also signal through the ability of the adaptor protein ?arrestin to scaffold signaling complexes that are distinct from canonical G protein signaling. These dual signaling modes may enable what is commonly referred to as functionally selective or biased signaling. We have shown before that the dopamine D2 receptor (D2R), which is the main target of clinically effective antipsychotics, mediates some of its physiological effects through engagement of a ?arrestin2/Akt/PP2A/GSK3? signaling complex. During the initial portion of this R37 award, we have used genetic, biochemical, and pharmacological approaches to provide concrete evidence that D2R/?arrestin2 signaling is important in behavioral responses following activation of the DA system. Interestingly, we discovered using neuronally selective deletions of ?arrestin2 in mice that an antipsychotic-like D2R/?arrestin2 biased tool compound UNC9994A behaved as an antagonist in the striatum but an agonist in the cortex. These results correlate with both higher levels of GPCR kinase and ?arrestin2 in cortex versus striatum and the ability of UNC9994A to reverse deficits in a mouse model of cognitive/sociability functions. These results suggest that ?arrestin2/D2R signaling may be an unappreciated means to control cognitive and social domains of behavior in vivo. The goals of our R37 continuation application are to use the genetic and biochemical tools we have developed, like G protein or ?arrestin2 preferring mutant D2Rs, to identify cell type specific molecular and biochemical mechanisms involved in the control of these behavioral domains.
Our Specific Aims are: 1) determine the impact of D2R biased signaling on cognitive domains in mice reconstituted with biased D2R mutants; 2) identify the molecular and neuronal mechanisms underpinning the cognitive and social effects and 3) assess how D2R biased signaling in the cortex controls neuronal electrophysiology and affects downstream brain circuits to control cognitive and sociability functions.

Public Health Relevance

Results obtained during the previous period have provided concrete evidence for a role of the dopamine D2 receptor/?arrestin2 signaling mode in the function of dopaminergic responses. Further studies aimed at understanding the contributions of this signaling mode in specific neurons will provide a better appreciation of how the brain's dopamine system controls critical behavioral domains often disrupted in human conditions.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Winsky, Lois M
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Duke University
Anatomy/Cell Biology
Schools of Medicine
United States
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Urs, Nikhil M; Gee, Steven M; Pack, Thomas F et al. (2016) Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties. Proc Natl Acad Sci U S A 113:E8178-E8186
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Dzirasa, Kafui; Krishnan, Ranga R; Williams, R Sanders (2015) Incubating the research independence of a medical scientist training program graduate: a case study. Acad Med 90:176-9
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Peterson, Sean M; Pack, Thomas F; Wilkins, Angela D et al. (2015) Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor. Proc Natl Acad Sci U S A 112:7097-102
Sutton, Laurie P; Caron, Marc G (2015) Essential role of D1R in the regulation of mTOR complex1 signaling induced by cocaine. Neuropharmacology 99:610-9
Peterson, Sean M; Pack, Thomas F; Caron, Marc G (2015) Receptor, Ligand and Transducer Contributions to Dopamine D2 Receptor Functional Selectivity. PLoS One 10:e0141637
Urs, Nikhil M; Bido, Simone; Peterson, Sean M et al. (2015) Targeting β-arrestin2 in the treatment of L-DOPA-induced dyskinesia in Parkinson's disease. Proc Natl Acad Sci U S A 112:E2517-26
Burczyk, Martina; Burkhalter, Martin D; Blätte, Tamara et al. (2015) Phenotypic regulation of the sphingosine 1-phosphate receptor miles apart by G protein-coupled receptor kinase 2. Biochemistry 54:765-75
Urs, Nikhil M; Nicholls, Peter J; Caron, Marc G (2014) Integrated approaches to understanding antipsychotic drug action at GPCRs. Curr Opin Cell Biol 27:56-62

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