Biogenic amine transporters are responsible for the reuptake and recycling of dopamine, norepinephrine and serotonin after their release from neurons. Plasma membrane biogenic amine transporters belong to a large family of Na+ and Cl- dependent transporters for neurotransmitters and amino acids. Inhibition of biogenic amine transporters by substances such as antidepressants or cocaine has profound behavioral effects, as does exchange mediated by the transporters between their natural substrate and amphetamine derivatives. In particular, the serotonin transporter (SERT) is sensitive to inhibition by cocaine and antidepressant drugs like imipramine and fluoxetine (Prozac), and exchanges intracellular serotonin (5- hydroxytryptamine, 5-HT) with external amphetamine and its analogs such as 3,4- methylenedioxymethamphetamine (MDMA), also known as """"""""ecstasy"""""""". Although much progress has been made in understanding the reaction catalyzed by SERT and its coupling to Na+, Cl- and K+ ions, the fundamental mechanism remains only a hypothesis that the transporter contains a binding site with alternating access to intracellular and extracellular media. Recently, a high resolution crystal structure has become available for a prokaryotic homologue of SERT. This structure provides a model for experiments designed to understand mechanistic and structural properties of mammalian neurotransmitter transporters. This application will examine the predictions of the structural model and will use that model to investigate the mechanism of serotonin transport.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA007259-17
Application #
7808009
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Pilotte, Nancy S
Project Start
1991-12-15
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
17
Fiscal Year
2010
Total Cost
$321,136
Indirect Cost
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Zhang, Yuan-Wei; Turk, Benjamin E; Rudnick, Gary (2016) Control of serotonin transporter phosphorylation by conformational state. Proc Natl Acad Sci U S A 113:E2776-83
Tavoulari, Sotiria; Margheritis, Eleonora; Nagarajan, Anu et al. (2016) Two Na+ Sites Control Conformational Change in a Neurotransmitter Transporter Homolog. J Biol Chem 291:1456-71
Sandtner, Walter; Stockner, Thomas; Hasenhuetl, Peter S et al. (2016) Binding Mode Selection Determines the Action of Ecstasy Homologs at Monoamine Transporters. Mol Pharmacol 89:165-75
Fenollar-Ferrer, Cristina; Stockner, Thomas; Schwarz, Thomas C et al. (2014) Structure and regulatory interactions of the cytoplasmic terminal domains of serotonin transporter. Biochemistry 53:5444-60
Rudnick, Gary; Krämer, Reinhard; Blakely, Randy D et al. (2014) The SLC6 transporters: perspectives on structure, functions, regulation, and models for transporter dysfunction. Pflugers Arch 466:25-42
Porton, B; Greenberg, B D; Askland, K et al. (2013) Isoforms of the neuronal glutamate transporter gene, SLC1A1/EAAC1, negatively modulate glutamate uptake: relevance to obsessive-compulsive disorder. Transl Psychiatry 3:e259
Rudnick, Gary (2013) How do transporters couple solute movements? Mol Membr Biol 30:355-9
Schicker, Klaus; Uzelac, Zeljko; Gesmonde, Joan et al. (2012) Unifying concept of serotonin transporter-associated currents. J Biol Chem 287:438-45
Bulling, Simon; Schicker, Klaus; Zhang, Yuan-Wei et al. (2012) The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters. J Biol Chem 287:18524-34
Rudnick, Gary (2011) Cytoplasmic permeation pathway of neurotransmitter transporters. Biochemistry 50:7462-75

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