Ttie proposed Core will continue to provide the biophysical-technical infrastructures and intellectual support required to test the novel hypotheses of this proposal that are relevant to the structure-function and functional regulation ofthe dopamine (DA) transporter (DAT). DAT is the major molecular target responsible forthe rewarding properties and abuse potential of amphetamine (AMPH), cocaine, and related psychostimulants. AMPH, as a result of its ability to reverse the inward transport of DA, is believed to induce DA efflux and therefore to increase extracellular DA levels. Thus, the long-term goals ofthe Core research team are to enable the PPG Consortium of Investigators (COI) to determine the cellular/structural bases of substrate efflux induced by AMPH. The Core will continue to be a resource and to develop state of the art technologies to address key experimental approaches in a unified and coordinated manner for the investigators ofthe PPG. The Core will ensure access to advanced technologies focused on the mechanisms of DATs in a manner that allows for comparisons among laboratories and between systems. The Core will also support and unify collaborative efforts among the members ofthe COI to facilitate them to address complex experiments and together overcome experimental difficulties throughout the PPG. These activities ofthe Core will continue to foster synergy between the different research groups of this project. Finally, the Core is devoted to increasing the availability of new approaches to strengthen the ability of the COI to answer both ongoing collaborative efforts as well as new scientific directions.

Public Health Relevance

Stimulant abuse and potentially other dopamine (DA)-related pathologies such as schizophrenia, are a tremendous public health burden. The DA transporter (DAT), which regulates extracellular brain DA, Is the major molecular target of several psychoactive drugs. Including amphetamine (AMPH). This proposal will analyze how AMPH by altering DAT function disrupts DA homeostasis possibly leading to addiction

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-G)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
New York
United States
Zip Code
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
Doktorova, M; Harries, D; Khelashvili, G (2017) Determination of bending rigidity and tilt modulus of lipid membranes from real-space fluctuation analysis of molecular dynamics simulations. Phys Chem Chem Phys 19:16806-16818
Razavi, Asghar M; Khelashvili, George; Weinstein, Harel (2017) A Markov State-based Quantitative Kinetic Model of Sodium Release from the Dopamine Transporter. Sci Rep 7:40076
Runegaard, Annika H; Jensen, Kathrine L; Fitzpatrick, Ciarán M et al. (2017) Preserved dopaminergic homeostasis and dopamine-related behaviour in hemizygous TH-Cre mice. Eur J Neurosci 45:121-128
Rahbek-Clemmensen, Troels; Lycas, Matthew D; Erlendsson, Simon et al. (2017) Super-resolution microscopy reveals functional organization of dopamine transporters into cholesterol and neuronal activity-dependent nanodomains. Nat Commun 8:740
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
Li, Xue; Maretzky, Thorsten; Perez-Aguilar, Jose Manuel et al. (2017) Structural modeling defines transmembrane residues in ADAM17 that are crucial for Rhbdf2-ADAM17-dependent proteolysis. J Cell Sci 130:868-878
LeVine, Michael V; Cuendet, Michel A; Khelashvili, George et al. (2016) Allosteric Mechanisms of Molecular Machines at the Membrane: Transport by Sodium-Coupled Symporters. Chem Rev 116:6552-87
Vuorenpää, Anne; Jørgensen, Trine N; Newman, Amy H et al. (2016) Differential Internalization Rates and Postendocytic Sorting of the Norepinephrine and Dopamine Transporters Are Controlled by Structural Elements in the N Termini. J Biol Chem 291:5634-51

Showing the most recent 10 out of 137 publications