Lena Sørensen

Education and employment

09/2002 – 03/2008: M.Sc. (pharm), Faculty of Pharmaceutical Sciences, University of Copenhagen

02/2007 – 12/2007: M.Sc student, Institute for Molecular Bioscience, University of Queensland, Australia

05/2008: Ph.D student, Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen  

Functional consequences of post-translational modification of SLC6 family neurotransmitter transporters

Background
Neurotransmission in the central nervous system (CNS) requires precise control of the duration and the magnitude of extracellular neurotransmitter concentrations. At the molecular level, a major control mechanism is active re-uptake of transmitters by integral membrane neurotransmitter transporters belonging to the solute carrier 6 (SLC6) family. These include specific transporters for the neurotransmitters serotonin, norepinephrine, dopamine, glycine and γ-aminobutyric acid. These transporters are important targets for therapeutics used in the treatment of numerous psychiatric and neurological diseases.

Emerging evidence indicates that spatiotemporal regulation of neurotransmitter transporter function and surface expression is a key mechanism for tuning of neurotransmitter signals for normal brain function^1,2. For the majority of SLC6 family neurotransmitter transporters, activation of several intracellular secondary signalling pathways can lead to acute up- or down regulation of transporter function and/or transporter surface levels through redistribution of transporter protein between intracellular stores and the plasma membrane. At the single transporter level, it appears that these processes require changes in transporter posttranslational modifications, specifically protein phosphorylation states, and interactions with intracellular proteins such as trafficking chaperones and scaffolding proteins^3-5. However, the molecular basis of these processes is poorly understood for several SLC6 family transporters.

Project
The present study will focus on characterizing the biochemical basis for SLC6 transporter regulation with focus on the role of phosphorylation and protein-protein interactions for regulation of basal transporter physiology. The majority of SLC6 transporters are known to be subject to direct protein phosphorylation by serine/threonine- and tyrosine kinases^4,6-8. However, the localization of specific phosphorylation sites is still unknown for many of these transporters. In this project, we aim to identify novel phosphorylation sites in selected SLC6 transporters.

1. Blakely, R.D. et al. Regulated phosphorylation and trafficking of antidepressant-sensitive serotonin transporter proteins. Biol Psychiatry 44, 169-78 (1998).
2. Kanner, B.I. Structure and function of sodium-coupled GABA and glutamate transporters. J Membr Biol 213, 89-100 (2006).
3. Hu, J. & Quick, M.W. Substrate-mediated regulation of gamma-aminobutyric acid transporter 1 in rat brain. Neuropharmacology (2007).
4. Foster, J.D., Cervinski, M.A., Gorentla, B.K. & Vaughan, R.A. Regulation of the dopamine transporter by phosphorylation. Handb Exp Pharmacol, 197-214 (2006).
5. Jayanthi, L.D. & Ramamoorthy, S. Regulation of monoamine transporters: influence of psychostimulants and therapeutic antidepressants. Aaps J 7, E728-38 (2005).
6. Ramamoorthy, S., Samuvel, D.J., Buck, E.R., Rudnick, G. & Jayanthi, L.D. Phosphorylation of threonine residue 276 is required for acute regulation of serotonin transporter by cyclic GMP. J Biol Chem 282, 11639-47 (2007).
7. Whitworth, T.L. & Quick, M.W. Substrate-induced regulation of gamma-aminobutyric acid transporter trafficking requires tyrosine phosphorylation. J Biol Chem 276, 42932-7 (2001).
8. Jayanthi, L.D., Annamalai, B., Samuvel, D.J., Gether, U. & Ramamoorthy, S. Phosphorylation of the norepinephrine transporter at threonine 258 and serine 259 is linked to protein kinase C-mediated transporter internalization. J Biol Chem 281, 23326-40 (2006).

Main Supervisor:
Kristian Strømgaard, Ph. D.
Professor
Department of Medicinal Chemistry

Co-supervisor:
Anders Skov Kristensen, Ph. D.
Ass. Professor
Department of Medicinal Chemistry