The catecholamine dopamine (DA) plays a key role in the regulation of cognitive, emotional, and behavioral functions, and abnormalities in its regulation have been implicated in several psychiatric and neurological disorders. DA exerts it actions at D2-like and D1-like receptors, members of the G protein-coupled receptor (GPCR) family. DA reuptake by the DA transporter (DAT) is a principal mechanism for terminating dopaminergic transmission, and this protein is the primary molecular target of amphetamine, cocaine, and other psychostimulants. The Javitch laboratory studies structure-function relations and mechanisms of regulation of neurotransmitter transporters and related bacterial transporters, as well as mechanisms of dopamine receptor oligomerization and function. His long-term research goals are to: 1) Understand the structural bases of agonist and antagonist binding and specificity in G protein-coupled receptors, with a current focus on dopamine and opioid receptors. 2) Determine how agonist binding is transduced into G-protein activation. 3) Determine the structural bases of substrate translocation and inhibitor binding to the dopamine transporter. 4) Determine the mechanistic bases of amphetamine-induced dopamine efflux and the role of regulation of these processes in sensitization. The K Award enables the candidate to devote focused efforts to the exploration of new approaches, novel systems and various multidisciplinary methods and collaborations aimed at one of the central goals of the research program in the laboratory - the mechanisms of drugs of abuse. In collaboration with leading experts, individuals in the candidate's laboratory are now pursuing membrane protein crystallography and electron paramagnetic resonance &single molecule fluorescence spectroscopy of bacterial homologs of neurotransmitter transporter and are also pursuing work in knock-in mice and transgenic flies as model systems to probe molecular and mechanistic insights in a physiological background. These new approaches are being developed and used to lay the groundwork to maintain the candidate's research at the leading edge of the field of molecular mechanisms of drug abuse and actions of antipsychotic drugs. The support of the K05 Award would play an essential role in the candidate's continued growth by giving him the flexibility to focus in part outside of the area of his current methodologies and to fuse his own professional growth with that of his research program and his trainees.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Award (K05)
Project #
5K05DA022413-05
Application #
8123234
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Satterlee, John S
Project Start
2007-09-15
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$123,055
Indirect Cost
Name
Columbia University (N.Y.)
Department
Psychiatry
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Yano, Hideaki; Provasi, Davide; Cai, Ning Sheng et al. (2017) Development of novel biosensors to study receptor-mediated activation of the G-protein ? subunits Gs and Golf. J Biol Chem 292:19989-19998
Zheng, Qinsi; Jockusch, Steffen; Zhou, Zhou et al. (2017) Electronic tuning of self-healing fluorophores for live-cell and single-molecule imaging. Chem Sci 8:755-762
Aguilar, Jenny I; Dunn, Matthew; Mingote, Susana et al. (2017) Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT. Neuron 95:1074-1088.e7
Stolzenberg, Sebastian; Li, Zheng; Quick, Matthias et al. (2017) The role of transmembrane segment 5 (TM5) in Na2 release and the conformational transition of neurotransmitter:sodium symporters toward the inward-open state. J Biol Chem 292:7372-7384
Sykes, David A; Moore, Holly; Stott, Lisa et al. (2017) Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors. Nat Commun 8:763
Karam, Caline S; Sen, Namita; Javitch, Jonathan A (2017) Phospho-specific antibodies targeting the amino terminus of the human dopamine transporter. J Chem Neuroanat 83-84:91-98
Abdallah, Chadi G; Hannestad, Jonas; Mason, Graeme F et al. (2017) Metabotropic Glutamate Receptor 5 and Glutamate Involvement in Major Depressive Disorder: A Multimodal Imaging Study. Biol Psychiatry Cogn Neurosci Neuroimaging 2:449-456
Gregorio, G Glenn; Masureel, Matthieu; Hilger, Daniel et al. (2017) Single-molecule analysis of ligand efficacy in ?2AR-G-protein activation. Nature 547:68-73
Michino, Mayako; Boateng, Comfort A; Donthamsetti, Prashant et al. (2017) Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D3 Receptor. J Med Chem 60:580-593
LeVine, Michael V; Khelashvili, George; Shi, Lei et al. (2016) Role of Annular Lipids in the Functional Properties of Leucine Transporter LeuT Proteomicelles. Biochemistry 55:850-9

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