The structural, functional and sheer mechanistic complexity of the neurotransmitter transporters (NTs) remains a significant challenge that we must continue to address because these cell components are responsible, as a class - the Neurotransmitter : Sodium Symporter (NSS) - and individually (DAT, SERT, NET) for major aspects of neuronal function in the brain. These membrane proteins play essential roles in cell signaling and, not surprisingly, are primary targets for medications (e.g., the antidepressants) as well as for abused drugs including the psychostimulants cocaine and amphetamine. The organization of the PPG and its Research Plan, in the 3 individual Projects and the 2 Cores, recognizes the rapid and abundant new developments in the field and new opportunities to understand the mechanisms of the NTs in the physiological processes underlying neurotransmission in general, and their involvement in drug addiction and abuse in particular. The long-term goals are to understand how the accumulation and efflux of neurotransmitters (e.g., dopamine) are regulated by post-translational modification of the NTs (DAT), by their association with other proteins, and by their localization to specific membrane micro-domains. Mechanistic details are sought to understand the molecular and cellular processes governing the activity and availability of the NTs, such as DAT, in the presynaptic membrane, and how these processes are altered in diseased states involving signaling dysfunction. With appreciation for the multidisciplinary, multiscale strategies required to achieve such goals, this renewal application builds upon the collaborative acumen and synergies established in the PPG consortium, and widens the focus to include elucidation of functional mechanisms in large membrane assemblies (Project 1), whole cells, tissues, and even whole animals (Projects 2&3 and Core B). To address these mechanisms in DAT and SERT, our research plan leverages as well new methodology, major equipment and expertise in many cognate areas, through extensive collaborations that the participating labs have established to create a multidisciplinary team even larger than the PPG, which that enhances and widens the power and scope of the innovative research proposed in this application.

Public Health Relevance

The dopamine transporter is responsible for the rewarding properties and abuse potential of cocaine, amphetamine, and related psychostimulants. The related transporters for serotonin and norepinephrine are targets for antidepressant medications and secondary targets for psychostimulants. We strive to understand how these transporters are regulated in health and in disease. OVERALL PROJECT

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
2P01DA012408-12
Application #
8018714
Study Section
Special Emphasis Panel (ZRG1-MDCN-G (51))
Program Officer
Hillery, Paul
Project Start
1999-07-09
Project End
2016-02-29
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
12
Fiscal Year
2011
Total Cost
$995,241
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Physiology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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

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