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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Scientist Award (K05)
Project #
Application #
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Satterlee, John S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Schools of Medicine
New York
United States
Zip Code
Niswender, Colleen M; Jones, Carrie K; Lin, Xin et al. (2016) Development and Antiparkinsonian Activity of VU0418506, a Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor 4 Homomers without Activity at mGlu2/4 Heteromers. ACS Chem Neurosci 7:1201-11
Khelashvili, George; Schmidt, Solveig Gaarde; Shi, Lei et al. (2016) Conformational Dynamics on the Extracellular Side of LeuT Controlled by Na+ and K+ Ions and the Protonation State of Glu290. J Biol Chem 291:19786-99
Freyberg, Zachary; Sonders, Mark S; Aguilar, Jenny I et al. (2016) Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain. Nat Commun 7:10652
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
Farino, Zachary J; Morgenstern, Travis J; Vallaghe, Julie et al. (2016) Development of a Rapid Insulin Assay by Homogenous Time-Resolved Fluorescence. PLoS One 11:e0148684
DeLorenzo, Christine; Gallezot, Jean-Dominique; Gardus, John et al. (2016) 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 :
Zou, Mu-Fa; Keck, Thomas M; Kumar, Vivek et al. (2016) Novel Analogues of (R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (Sumanirole) Provide Clues to Dopamine D2/D3 Receptor Agonist Selectivity. J Med Chem 59:2973-88
Klein Herenbrink, Carmen; Sykes, David A; Donthamsetti, Prashant et al. (2016) The role of kinetic context in apparent biased agonism at GPCRs. Nat Commun 7:10842
Kruegel, Andrew C; Gassaway, Madalee M; Kapoor, Abhijeet et al. (2016) Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators. J Am Chem Soc 138:6754-64
Frederick, A L; Yano, H; Trifilieff, P et al. (2015) Evidence against dopamine D1/D2 receptor heteromers. Mol Psychiatry 20:1373-85

Showing the most recent 10 out of 84 publications