The 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 of the dopamine (DA) transporter (DAT). DAT is the major molecular target responsible for the 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 of the 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 of the 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 of the COI to facilitate them to address complex experiments and together overcome experimental difficulties throughout the PPG. These activities of the 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.
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.
|Kazmier, Kelli; Sharma, Shruti; Quick, Matthias et al. (2014) Conformational dynamics of ligand-dependent alternating access in LeuT. Nat Struct Mol Biol 21:472-9|
|Hansen, Freja H; Skjørringe, Tina; Yasmeen, Saiqa et al. (2014) Missense dopamine transporter mutations associate with adult parkinsonism and ADHD. J Clin Invest 124:3107-20|
|Johner, Niklaus; Mondal, Sayan; Morra, Giulia et al. (2014) Protein and lipid interactions driving molecular mechanisms of in meso crystallization. J Am Chem Soc 136:3271-84|
|Hamilton, Peter J; Belovich, Andrea N; Khelashvili, George et al. (2014) PIP2 regulates psychostimulant behaviors through its interaction with a membrane protein. Nat Chem Biol 10:582-9|
|Jørgensen, Trine Nygaard; Christensen, Peter Møller; Gether, Ulrik (2014) Serotonin-induced down-regulation of cell surface serotonin transporter. Neurochem Int 73:107-12|
|LeVine, Michael V; Weinstein, Harel (2014) NbIT--a new information theory-based analysis of allosteric mechanisms reveals residues that underlie function in the leucine transporter LeuT. PLoS Comput Biol 10:e1003603|
|Erlendsson, Simon; Rathje, Mette; Heidarsson, Pétur O et al. (2014) Protein interacting with C-kinase 1 (PICK1) binding promiscuity relies on unconventional PSD-95/discs-large/ZO-1 homology (PDZ) binding modes for nonclass II PDZ ligands. J Biol Chem 289:25327-40|
|Pinheiro, Paulo S; Jansen, Anna M; de Wit, Heidi et al. (2014) The BAR domain protein PICK1 controls vesicle number and size in adrenal chromaffin cells. J Neurosci 34:10688-700|
|Dehnes, Yvette; Shan, Jufang; Beuming, Thijs et al. (2014) Conformational changes in dopamine transporter intracellular regions upon cocaine binding and dopamine translocation. Neurochem Int 73:4-15|
|Rahbek-Clemmensen, Troels; Bay, Tina; Eriksen, Jacob et al. (2014) The serotonin transporter undergoes constitutive internalization and is primarily sorted to late endosomes and lysosomal degradation. J Biol Chem 289:23004-19|
Showing the most recent 10 out of 109 publications