This Project of the PPG is devoted to the structural context of the mechanistic study of Na+/Cl- dependent biogenic amine transporters (NT) function. We will investigate - for DAT, SERT, and NET - the role of specific structural elements in the physiological processes underlying neurotransmission and mechanisms in drug addiction and abuse, with generalizations and comparisons to other NTs. The proposed studies use 3D modeling and computational analysis of dynamics and energetics to achieve, in close collaboration with the other PPG projects, a quantitative evaluation of the structural and energetic basis for: (i) the role of specific sets of both intra- and inter-molecular interactions of N-termini, C-termini and key loops of NTs in experimentally measured properties that underlie function, and the changes that are produced by phosphorylation (SA #1a), and (ii) the detailed mode of interaction and specificity for interactions with PDZ domains considered to be involved in internalization, recycling, sorting, stabilization of NT, and in regulation of NT function. We will investigate steric and dynamic properties of NT C-terminal interaction with PDZ domains (starting with DAT-PICK1 interactions), and the molecular determinants for regulation of interactions selectivity by phosphorylation (of either the peptide or the PDZ) (SA #1b). The considerable amounts and variety of data prompt us to build two modes of empowering representation: a) 3D models based on structure-informed working hypotheses, refined bioinformatics approaches and computational molecular biophysics algorithms, constraints from functional insights obtained in the PPG and the literature, and newly published structural information from x-ray and EM studies of transporter and membrane protein systems that can be used as guides for structural principles in 3D modeling and as probes for validation of approaches (SA #2), and b) a transporter-centric information management system (TIMS) to serve as an electronic catalog of quantitative data about NT interactions (with ligands: substrates, blockers and modulators, and cell components such as scaffolding proteins), as well as NT activities (e.g., substrate transport rates under various conditions and NT states) and other quantitative data obtained in the PPG Projects (SA #3).

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
2P01DA012408-07
Application #
6880178
Study Section
Special Emphasis Panel (ZDA1-RXL-E (06))
Project Start
2004-12-01
Project End
2010-12-31
Budget Start
2004-12-01
Budget End
2006-12-31
Support Year
7
Fiscal Year
2005
Total Cost
$187,480
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Mayer, Felix P; Schmid, Diethart; Owens, W Anthony et al. (2018) An unsuspected role for organic cation transporter 3 in the actions of amphetamine. Neuropsychopharmacology 43:2408-2417
Quick, Matthias; Abramyan, Ara M; Wiriyasermkul, Pattama et al. (2018) The LeuT-fold neurotransmitter:sodium symporter MhsT has two substrate sites. Proc Natl Acad Sci U S A 115:E7924-E7931
Herborg, Freja; Andreassen, Thorvald F; Berlin, Frida et al. (2018) Neuropsychiatric disease-associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes. J Biol Chem 293:7250-7262
Razavi, Asghar M; Khelashvili, George; Weinstein, Harel (2018) How structural elements evolving from bacterial to human SLC6 transporters enabled new functional properties. BMC Biol 16:31
Doktorova, Milka; Weinstein, Harel (2018) Accurate In Silico Modeling of Asymmetric Bilayers Based on Biophysical Principles. Biophys J 115:1638-1643
LeVine, Michael V; Cuendet, Michel A; Razavi, Asghar M et al. (2018) Thermodynamic Coupling Function Analysis of Allosteric Mechanisms in the Human Dopamine Transporter. Biophys J 114:10-14
Wragg, Rachel T; Parisotto, Daniel A; Li, Zhenlong et al. (2017) Evolutionary Divergence of the C-terminal Domain of Complexin Accounts for Functional Disparities between Vertebrate and Invertebrate Complexins. Front Mol Neurosci 10:146
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
Runegaard, Annika H; Jensen, Kathrine L; Fitzpatrick, CiarĂ¡n M et al. (2017) Preserved dopaminergic homeostasis and dopamine-related behaviour in hemizygous TH-Cre mice. Eur J Neurosci 45:121-128
Jensen, Kathrine L; Runegaard, Annika H; Weikop, Pia et al. (2017) Assessment of Dopaminergic Homeostasis in Mice by Use of High-performance Liquid Chromatography Analysis and Synaptosomal Dopamine Uptake. J Vis Exp :

Showing the most recent 10 out of 146 publications