Molekulare Mechanismen und zelluläre Funktionen EAAT-assoziierter Anionenkanäle

• Applicant: Professor Dr. Christoph Fahlke
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2009 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 108953003

• Final Report Year: 2014

Final Report Abstract

Die Hauptziele des Sachmittelantrages waren die Beschreibung der EAAT Anionenpore auf molekularer Ebene und Einblicke in mögliche physiologische Aufgaben dieser besonderen Transportfunktion. Diese beiden Hauptziele wurden vollständig erfüllt. Wir haben durch eine Kombination aus molecular dynamics simulation und funktionellen Untersuchungen die Anionenpore molekular beschrieben. Darüber hinaus konnten wir durch die funktionelle Analyse von krankheitsverursachenden Punktmutationen eine physiologische Funktion postulieren, die wir zurzeit durch Tiermodelle testen.

Publications

• (2010) A conserved aspartate determines pore properties of anion channels associated with excitatory amino acid transporter 4 (EAAT4). J Biol Chem 285, 23676-23686
  Kovermann, P., Machtens, J. P., Ewers, D., and Fahlke, Ch.
  
• (2011) Hetero-oligomerization of neuronal glutamate transporters. J Biol Chem 286, 3935-3943
  Nothmann, D., Leinenweber, A., Torres-Salazar, D., Kovermann, P., Hotzy, J., Gameiro, A., Grewer, C., and Fahlke, Ch.
  
• (2011) Noise analysis to study unitary properties of transporter-associated ion channels. Channels (Austin.) 5, 468-472
  Machtens, J. P., Fahlke, Ch., and Kovermann, P.
  
• (2011) Regulation of glial glutamate transporters by C-terminal domains. J Biol Chem 286, 1927-1937
  Leinenweber, A., Machtens, J. P., Begemann, B., and Fahlke, Ch.
  
• (2011) Substrate-dependent Gating of Anion Channels Associated with Excitatory Amino Acid Transporter 4. J Biol Chem 286, 23780-23788
  Machtens, J. P., Kovermann, P., and Fahlke, Ch.
  
• (2012) A point mutation associated with episodic ataxia 6 increases glutamate transporter anion currents. Brain 135, 3416-3425
  Winter, N., Kovermann, P., and Fahlke, Ch.
  (See online at https://doi.org/10.1093/brain/aws255)
• (2012) Neutralizing aspartate 83 modifies substrate translocation of excitatory amino acid transporter 3 (EAAT3) glutamate transporters. J Biol Chem 287, 20016-20026
  Hotzy, J., Machtens, J. P., and Fahlke, Ch.
  (See online at https://doi.org/10.1074/jbc.M112.344077)
• (2013) Allosteric modulation of an excitatory amino acid transporter: the subtype-selective inhibitor UCPH-101 exerts sustained inhibition of EAAT1 through an intramonomeric site in the trimerization domain. J Neurosci 33, 1068-1087
  Abrahamsen, B., Schneider, N., Erichsen, M. N., Huynh, T. H., Fahlke, Ch., Bunch, L., and Jensen, A. A.
  (See online at https://doi.org/10.1523/JNEUROSCI.3396-12.2013)
• (2013) Induced fit substrate binding to an archeal glutamate transporter homologue. Proc Natl Acad Sci USA 110, 12486-12491
  Ewers, D., Becher, T., Machtens, J. P., Weyand, I., and Fahlke, Ch.
  (See online at https://doi.org/10.1073/pnas.1300772110)
• (2013) Mutating a conserved proline residue within the trimerization domain modifies Na+ binding to excitatory amino acid transporters and associated conformational changes. J Biol Chem 288, 36492-36501
  Hotzy, J., Schneider, N., Kovermann, P., and Fahlke, Ch.
  (See online at https://doi.org/10.1074/jbc.M113.489385)
• (2014) Functional properties of the retinal glutamate transporters GLT-1c and EAAT5. J Biol Chem 289, 1815
  Schneider, N., Cordeiro, S., Machtens, J. P., Braams, S., Rauen, T., and Fahlke, Ch.
  (See online at https://doi.org/10.1074/jbc.M113.517177)