This is an application for the NIDA sponsored K02 Independent Scientist Award. The long term goal of the candidate is to elucidate the mechanisms of G protein signaling regulation in the basal ganglia as a necessary prerequisite to understanding neurological diseases and addiction and developing means of their treatment. The main focus of the research proposal is on the central regulator of opioid and dopamine G protein signaling, RGS9-2 that has been implicated in addiction and drug abuse. We have recently discovered that RGS9-2 in the striatum exists in a complex with a novel neuronal protein which we named R7 Binding Protein (R7BP). The HYPOTHESIS addressed by this proposal is that R7BP serves as a critical regulator of RGS9-2 function in the striatal neurons by controlling the expression level, localization, and activity of RGS9-2. This hypothesis will be addressed in the following SPECIFIC AIMS: 1. to determine the mechanisms by which R7BP controls expression of RGS9-2 in striatal neurons. 2. To understand the role of R7BP in the regulation of RGS9-2 catalytic activity. 3. To further characterize the molecular composition of G protein inactivating complex in striatal neurons. In addition to pursuing the research goals, the applicant plans to undertake career development activities by: (I) establishing and/or maintaining active collaborations with leading researchers focusing on drug addiction mechanisms, (II) integrating my research program into the larger community efforts to understand mechanisms of drug addiction and (III) learning cutting edge behavioral and imaging approaches to study drug addiction and implanting them to pursue the research directions in the laboratory.

Public Health Relevance

The studies should provide an insight into the mechanisms that regulate reward processing in the basal ganglia of the brain. This knowledge will be important for better understanding of how drugs of abuse lead to addiction with the hopes for the future development of therapeutical intervention strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02DA026405-05
Application #
8235864
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Hillery, Paul
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$121,500
Indirect Cost
$9,000
Name
Scripps Florida
Department
Type
DUNS #
148230662
City
Jupiter
State
FL
Country
United States
Zip Code
33458
Ostrovskaya, Olga; Xie, Keqiang; Masuho, Ikuo et al. (2014) RGS7/G?5/R7BP complex regulates synaptic plasticity and memory by modulating hippocampal GABABR-GIRK signaling. Elife 3:e02053
Kumar, Kishore R; Lohmann, Katja; Masuho, Ikuo et al. (2014) Mutations in GNAL: a novel cause of craniocervical dystonia. JAMA Neurol 71:490-4
Masuho, Ikuo; Xie, Keqiang; Martemyanov, Kirill A (2013) Macromolecular composition dictates receptor and G protein selectivity of regulator of G protein signaling (RGS) 7 and 9-2 protein complexes in living cells. J Biol Chem 288:25129-42
Fuchs, Tania; Saunders-Pullman, Rachel; Masuho, Ikuo et al. (2013) Mutations in GNAL cause primary torsion dystonia. Nat Genet 45:88-92
Xie, Keqiang; Ge, Shencheng; Collins, Victoria E et al. (2012) Gýý5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems. Psychopharmacology (Berl) 219:823-34
Posokhova, Ekaterina; Song, Hongman; Belcastro, Marycharmain et al. (2011) Disruption of the chaperonin containing TCP-1 function affects protein networks essential for rod outer segment morphogenesis and survival. Mol Cell Proteomics 10:M110.000570
Cao, Yan; Posokhova, Ekaterina; Martemyanov, Kirill A (2011) TRPM1 forms complexes with nyctalopin in vivo and accumulates in postsynaptic compartment of ON-bipolar neurons in mGluR6-dependent manner. J Neurosci 31:11521-6
Masuho, Ikuo; Wakasugi-Masuho, Hideko; Posokhova, Ekaterina N et al. (2011) Type 5 G protein beta subunit (Gbeta5) controls the interaction of regulator of G protein signaling 9 (RGS9) with membrane anchors. J Biol Chem 286:21806-13
Masuho, Ikuo; Celver, Jeremy; Kovoor, Abraham et al. (2010) Membrane anchor R9AP potentiates GTPase-accelerating protein activity of RGS11 x Gbeta5 complex and accelerates inactivation of the mGluR6-G(o) signaling. J Biol Chem 285:4781-7
Cao, Yan; Kolesnikov, Alexander V; Masuho, Ikuo et al. (2010) Membrane anchoring subunits specify selective regulation of RGS9·Gbeta5 GAP complex in photoreceptor neurons. J Neurosci 30:13784-93

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