G protein signal transduction pathways in the striatum play a pivotal role in the development of drug addiction. Many drugs of abuse including opioids and psychostimulants produce their effects by activating G proteins in the striatum, a major reward-processing nucleus in the brain. Our long term goal is to elucidate molecular and cellular mechanisms that regulate signaling in the striatal G protein pathways as a necessary prerequisite to understanding events that lead to substance dependence and designing strategies for the therapeutic correction. Increasing evidence suggests that Regulators of G protein Signaling (RGS) proteins play a crucial role in controlling G protein signaling pathways implicated in addiction. RGS proteins serve to curb G protein signaling and thus are optimally positioned to naturally counteract excessive activation of the G protein coupled receptors by drugs of abuse. Small molecule therapeutics targeting RGS proteins are emerging as promising therapeutic strategies. However, the mechanisms of RGS action in regulation of striatal G protein pathways are poorly understood. This proposal is focused on delineating the mechanisms by which key striatal RGS proteins: RGS9-2 and RGS7 regulate cellular signaling. Our recent findings indicate that the function of the two RGS proteins is closely intertwined. They exist as macromolecular complexes with several binding partners and undergo striking remodeling upon drug exposure as well as changes in neuronal excitability suggesting that plasticity in the RGS system contributes to molecular adaptations leading to addiction. Based on accumulated preliminary data we hypothesize that striatal RGS9-2 and RGS7 in cooperation with their binding partners differentially regulate G protein signaling from opioid and dopamine receptors to the central downstream effector adenylyl cyclase and that the plasticity in this system is a critical determinant of the addictive drug actions. This hypothesis will be tested by pursuing three complementary Specific Aims that seek to (1) to determine mechanisms of cAMP regulation by striatal RGS complexes, (2) understand receptor and G protein selectivity of their action and (3) test the role CaMKII? in regulating plasticity of striatal RGS complexes. The strategy proposed to address these Aims will entail a synergistic combination of genetic, behavioral, biochemical, and physiological approaches, exploiting the existence of a powerful array of reagents and animal models.

Public Health Relevance

Drug addiction is a disorder of the brain that puts a heavy burden on society. Studies proposed herein are aimed at understanding molecular mechanisms controlling the function of the neuronal signaling systems that mediate the effects of addictive drugs. It is anticipated that the results will facilitate the design of novel strategies for the treatment of drug addiction and neurological diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA036596-01A1
Application #
8757937
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Hillery, Paul
Project Start
2014-09-15
Project End
2019-07-31
Budget Start
2014-09-15
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Scripps Florida
Department
Type
DUNS #
City
Jupiter
State
FL
Country
United States
Zip Code
33458
Hauser, Alexander S; Chavali, Sreenivas; Masuho, Ikuo et al. (2018) Pharmacogenomics of GPCR Drug Targets. Cell 172:41-54.e19
Muntean, Brian S; Zucca, Stefano; MacMullen, Courtney M et al. (2018) Interrogating the Spatiotemporal Landscape of Neuromodulatory GPCR Signaling by Real-Time Imaging of cAMP in Intact Neurons and Circuits. Cell Rep 24:1081-1084
Muntean, Brian S; Zucca, Stefano; MacMullen, Courtney M et al. (2018) Interrogating the Spatiotemporal Landscape of Neuromodulatory GPCR Signaling by Real-Time Imaging of cAMP in Intact Neurons and Circuits. Cell Rep 22:255-268
Qutob, Nouar; Masuho, Ikuo; Alon, Michal et al. (2018) RGS7 is recurrently mutated in melanoma and promotes migration and invasion of human cancer cells. Sci Rep 8:653
Song, Chenghui; Anderson, Garret R; Sutton, Laurie P et al. (2018) Selective Role of RGS9-2 in Regulating Retrograde Synaptic Signaling of Indirect Pathway Medium Spiny Neurons in Dorsal Striatum. J Neurosci 38:7120-7131
Patil, Dipak N; Rangarajan, Erumbi S; Novick, Scott J et al. (2018) Structural organization of a major neuronal G protein regulator, the RGS7-G?5-R7BP complex. Elife 7:
Marcott, Pamela F; Gong, Sheng; Donthamsetti, Prashant et al. (2018) Regional Heterogeneity of D2-Receptor Signaling in the Dorsal Striatum and Nucleus Accumbens. Neuron 98:575-587.e4
Himmelreich, Sophie; Masuho, Ikuo; Berry, Jacob A et al. (2017) Dopamine Receptor DAMB Signals via Gq to Mediate Forgetting in Drosophila. Cell Rep 21:2074-2081
Sutton, Laurie P; Ostrovskaya, Olga; Dao, Maria et al. (2016) Regulator of G-Protein Signaling 7 Regulates Reward Behavior by Controlling Opioid Signaling in the Striatum. Biol Psychiatry 80:235-45
Shamseldin, Hanan E; Masuho, Ikuo; Alenizi, Ahmed et al. (2016) GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition. Genome Biol 17:195

Showing the most recent 10 out of 21 publications