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 #
5P01DA010044-17
Application #
8377512
Study Section
Special Emphasis Panel (ZRG1-MDCN-G)
Project Start
Project End
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
17
Fiscal Year
2012
Total Cost
$254,309
Indirect Cost
Name
Rockefeller University
Department
Type
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Milosevic, Ana; Liebmann, Thomas; Knudsen, Margarete et al. (2016) Cell- and region-specific expression of depression-related protein p11 (S100a10) in the brain. J Comp Neurol :
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
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
Liu, Ruijie; Correll, Robert N; Davis, Jennifer et al. (2015) Cardiac-specific deletion of protein phosphatase 1β promotes increased myofilament protein phosphorylation and contractile alterations. J Mol Cell Cardiol 87:204-13
Uematsu, Ken; Heiman, Myriam; Zelenina, Marina et al. (2015) Protein kinase A directly phosphorylates metabotropic glutamate receptor 5 to modulate its function. J Neurochem 132:677-86
Engmann, Olivia; Giralt, Albert; Gervasi, Nicolas et al. (2015) DARPP-32 interaction with adducin may mediate rapid environmental effects on striatal neurons. Nat Commun 6:10099
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
Yamagata, Yoko; Nairn, Angus C (2015) Contrasting features of ERK1/2 activity and synapsin I phosphorylation at the ERK1/2-dependent site in the rat brain in status epilepticus induced by kainic acid in vivo. Brain Res 1625:314-23
Plattner, Florian; Hayashi, Kanehiro; Hernández, Adan et al. (2015) The role of ventral striatal cAMP signaling in stress-induced behaviors. Nat Neurosci 18:1094-100
Colangelo, Christopher M; Ivosev, Gordana; Chung, Lisa et al. (2015) Development of a highly automated and multiplexed targeted proteome pipeline and assay for 112 rat brain synaptic proteins. Proteomics 15:1202-14

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