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.
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.
|Hauser, Alexander S; Chavali, Sreenivas; Masuho, Ikuo et al. (2018) Pharmacogenomics of GPCR Drug Targets. Cell 172:41-54.e19|
|Ostrovskaya, Olga I; Orlandi, Cesare; Fajardo-Serrano, Ana et al. (2018) Inhibitory Signaling to Ion Channels in Hippocampal Neurons Is Differentially Regulated by Alternative Macromolecular Complexes of RGS7. J Neurosci 38:10002-10015|
|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|
|Dunn, Henry A; Patil, Dipak N; Cao, Yan et al. (2018) Synaptic adhesion protein ELFN1 is a selective allosteric modulator of group III metabotropic glutamate receptors in trans. Proc Natl Acad Sci U S A 115:5022-5027|
|Sarria, Ignacio; Cao, Yan; Wang, Yuchen et al. (2018) LRIT1 Modulates Adaptive Changes in Synaptic Communication of Cone Photoreceptors. Cell Rep 22:3562-3573|
|Wang, Yuchen; Fehlhaber, Katherine E; Sarria, Ignacio et al. (2017) The Auxiliary Calcium Channel Subunit ?2?4 Is Required for Axonal Elaboration, Synaptic Transmission, and Wiring of Rod Photoreceptors. Neuron 93:1359-1374.e6|
|Martemyanov, Kirill A; Sampath, Alapakkam P (2017) The Transduction Cascade in Retinal ON-Bipolar Cells: Signal Processing and Disease. Annu Rev Vis Sci 3:25-51|
Showing the most recent 10 out of 54 publications