The catecholamine dopamine (DA) plays a key role in the regulation of cognitive, emotional, and behavioral functions. Abnormalities in its regulation have been implicated in drug abuse as well as 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 relationships 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 DA and opioid receptors. 2) Determine how agonist binding is transduced into G-protein activation and arrestin recruitment and signaling. 3) Determine the structural bases of substrate translocation and inhibitor binding to neurotransmitter transporters and the dynamics associated with transport using biophysical and structural approaches in parallel with computational analysis. 4) Determine the mechanistic bases of AMPH-induced DA efflux and the role of regulation of these processes in sensitization and substance abuse. The K Award enables the candidate to devote focused effort to the exploration of new approaches, novel systems and various multi-disciplinary methods and collaborations aimed at one of the central goals of the research program in the laboratory - the mechanisms of drugs of abuse. The candidate's laboratory is pursuing membrane protein crystallography and electron paramagnetic resonance & single molecule fluorescence spectroscopy of bacterial homologs of neurotransmitter transporters. This work is now being extended to single molecule imaging of receptors in living cells. The lab is also pursuing work in genetically modified flies and mice as model systems to probe molecular and mechanistic insights in a physiological background. These new approaches are being developed and used 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 on expanding his research methodologies and to fuse his own professional growth with that of his research program as well as extensive mentorship of his trainees and junior faculty.

Public Health Relevance

This K05 Senior Scientist Award would support the continued career development and mentorship activities of an established Professor whose laboratory focuses on understanding the structure, function, and regulation of receptors and transporters and their role in the pathophysiology and potential therapeutics of drug abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Award (K05)
Project #
4K05DA022413-10
Application #
9120851
Study Section
Training and Career Development Subcommittee (NIDA)
Program Officer
Satterlee, John S
Project Start
2007-09-01
Project End
2017-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
10
Fiscal Year
2016
Total Cost
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
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
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
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
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
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
DeLorenzo, Christine; Gallezot, Jean-Dominique; Gardus, John et al. (2017) In vivo variation in same-day estimates of metabotropic glutamate receptor subtype 5 binding using [11C]ABP688 and [18F]FPEB. J Cereb Blood Flow Metab 37:2716-2727
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
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

Showing the most recent 10 out of 96 publications