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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37MH073853-11
Application #
9058306
Study Section
Special Emphasis Panel (NSS)
Program Officer
Winsky, Lois M
Project Start
2016-01-20
Project End
2020-12-31
Budget Start
2016-01-20
Budget End
2016-12-31
Support Year
11
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Duke University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Rose, Samuel J; Pack, Thomas F; Peterson, Sean M et al. (2017) Engineered D2R Variants Reveal the Balanced and Biased Contributions of G-Protein and ?-Arrestin to Dopamine-Dependent Functions. Neuropsychopharmacology :
Urs, Nikhil M; Peterson, Sean M; Caron, Marc G (2017) New Concepts in Dopamine D2 Receptor Biased Signaling and Implications for Schizophrenia Therapy. Biol Psychiatry 81:78-85
Zhu, Lu; AlmaƧa, Joana; Dadi, Prasanna K et al. (2017) ?-arrestin-2 is an essential regulator of pancreatic ?-cell function under physiological and pathophysiological conditions. Nat Commun 8:14295
Zhu, Lu; Rossi, Mario; Cui, Yinghong et al. (2017) Hepatic ?-arrestin 2 is essential for maintaining euglycemia. J Clin Invest 127:2941-2945
Hultman, Rainbo; Mague, Stephen D; Li, Qiang et al. (2016) Dysregulation of Prefrontal Cortex-Mediated Slow-Evolving Limbic Dynamics Drives Stress-Induced Emotional Pathology. Neuron 91:439-52
Urs, Nikhil M; Gee, Steven M; Pack, Thomas F et al. (2016) Distinct cortical and striatal actions of a ?-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties. Proc Natl Acad Sci U S A 113:E8178-E8186
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
Snyder, Joshua C; Pack, Thomas F; Rochelle, Lauren K et al. (2015) A rapid and affordable screening platform for membrane protein trafficking. BMC Biol 13:107
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
Urs, Nikhil M; Bido, Simone; Peterson, Sean M et al. (2015) Targeting ?-arrestin2 in the treatment of L-DOPA-induced dyskinesia in Parkinson's disease. Proc Natl Acad Sci U S A 112:E2517-26

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