Considerable evidence indicates that the acute and chronic actions of psychomotor stimulants (e.g. cocaine and amphetamine), as well as of other drugs of abuse, involve modulation of neurotransmission in mesolimbic and nigrostriatal dopamine systems. Our previous studies have revealed that a family of substrates for cAMP-dependent protein kinase, including DARPP-32, RCS (Regulator of Calmodulin Signaling, previously termed ARPP-21), and ARPP-16, are highly enriched in medium spiny neurons of the basal ganglia, including the neostriatum and nucleus accumbens. Our ongoing research has also identified a new member of this family of striatal phosphoproteins as RaplGAP, a protein involved in the control of the small GTPase Rap. Other ongoing work has identified critical roles for novel isoforms of the serine/threonine protein phosphatase PP2A in control of the nucleo-cytoplasmic trafficking of DARPP-32, a process that is critical for the ability of DARPP-32 to mediate the actions of pyschostimulants. Moreover, we have found that ARPP-16 interacts with and may act to inhibit PP2A. Since the serine/threonine protein phosphatase, PPI, is a direct target for DARPP-32, and RCS controls PP2B activity indirectly, this work indicates that dopamine action in striatal neurons is likely to be largely mediated via the control of protein phosphatases. To address questions raised by these ongoing studies we propose two broad Specific Aims in Project 3 of the Program Project Grant.
In Aim I we will study the role of Rap GTPase, and its modulators RapGAP and EPAC in the actions of psychostimulants.
In Aim II we will study the role of novel isoforms of PP2A in the actions of psychostimulants.
Aim II will also include analysis of novel functions of PPI isoforms, the targets for DARPP-32 in striatal neurons. Results from our studies will complement the other two Projects of this Program Project grant. In addition, we will also carry out a number of collaborative studies with Projects 1 and 2, including studies of WAVEI phosphorylation with Project 1 and phosphoproteomic studies of mGluRS-dependent signaling in striatal neurons.

Public Health Relevance

Together with the other projects, the proposed studies will lead to elucidation of the biochemical pathways through which drugs of abuse act in the brain, and to an increased likelihood that therapeutic agents will be developed that will prevent or reverse molecular adaptations within these pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA010044-19
Application #
8624677
Study Section
Special Emphasis Panel (ZRG1-MDCN-G)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
19
Fiscal Year
2014
Total Cost
$252,475
Indirect Cost
Name
Rockefeller University
Department
Type
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Ceglia, Ilaria; Lee, Ko-Woon; Cahill, Michael E et al. (2017) WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine. Proc Natl Acad Sci U S A 114:1395-1400
Milosevic, Ana; Liebmann, Thomas; Knudsen, Margarete et al. (2017) Cell- and region-specific expression of depression-related protein p11 (S100a10) in the brain. J Comp Neurol 525:955-975
Andrade, Erika C; Musante, Veronica; Horiuchi, Atsuko et al. (2017) ARPP-16 Is a Striatal-Enriched Inhibitor of Protein Phosphatase 2A Regulated by Microtubule-Associated Serine/Threonine Kinase 3 (Mast 3 Kinase). J Neurosci 37:2709-2722
Seo, J-S; Zhong, P; Liu, A et al. (2017) Elevation of p11 in lateral habenula mediates depression-like behavior. Mol Psychiatry :
Musante, Veronica; Li, Lu; Kanyo, Jean et al. (2017) Reciprocal regulation of ARPP-16 by PKA and MAST3 kinases provides a cAMP-regulated switch in protein phosphatase 2A inhibition. Elife 6:
Seo, J-S; Wei, J; Qin, L et al. (2017) Cellular and molecular basis for stress-induced depression. Mol Psychiatry 22:1440-1447
Rapanelli, Maximiliano; Frick, Luciana R; Horn, Kyla D et al. (2016) The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons. J Biol Chem 291:21042-21052
Virk, Michael S; Sagi, Yotam; Medrihan, Lucian et al. (2016) Opposing roles for serotonin in cholinergic neurons of the ventral and dorsal striatum. Proc Natl Acad Sci U S A 113:734-9
Lee, K-W; Westin, L; Kim, J et al. (2015) Alteration by p11 of mGluR5 localization regulates depression-like behaviors. Mol Psychiatry 20:1546-56
Lazenka, Matthew F; Tomarchio, Aaron J; Lichtman, Aron H et al. (2015) Role of Dopamine Type 1 Receptors and Dopamine- and cAMP-Regulated Phosphoprotein Mr 32 kDa in ?9-Tetrahydrocannabinol-Mediated Induction of ?FosB in the Mouse Forebrain. J Pharmacol Exp Ther 354:316-27

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