Glutamate is the major excitatory neurotransmitter in the mammalian brain and acts at the same time as one of the most powerful neurotoxins. In order to ensure a continuous communication between nerve cells, glutamate transporters are crucial for both the efficient removal of transmitter and the buffering of glutamate in the synaptic cleft during synaptic transmission. The buffering of glutamate subsequently influences the activation of different receptor classes in a spatio-temporal manner. In this context the rapid translocation of glutamate transporters between plasma membrane and intracellular compartments (membrane trafficking) is an interesting regulatory aspect for changes in cell surface localization. This highly dynamic mechanism is well-established for different glutamate receptor classes and associated with synaptic plasticity. In this thesis membrane trafficking of glial and neuronal glutamate transporters and its underlying regulative endo- and exocytic mechanisms were investigated in detail. Thereby a novel tyrosine-based adaptor protein complex 2 (AP2) binding motif - Y V N G G F - in the cytoplasmic C-terminus of glutamate transporter subtype EAAC1 was identified. The interaction between AP2 and its binding motif facilitates clathrin-mediated endocytosis of EAAC1, which is constitutively recycled between plasma membrane and endosomal structures under basal conditions. Additionally the activity of tyrosine kinases could be linked to the plasma membrane localization of EAAC1, suggesting the regulation of AP2-EAAC1 interaction by phosphorylation of the tyrosine residue within the identified binding motif. Furthermore it could be shown that cholesterol directly influences both endocytosis of EAAC1 and transporter functionality. Altogether the data offers new insights into modulatory mechanisms underlying glutamatergic neurotransmission and elucidation in regards to diseases of the central nervous system associated with glutamate toxicity.
| Identifer | oai:union.ndltd.org:uni-osnabrueck.de/oai:repositorium.ub.uni-osnabrueck.de:urn:nbn:de:gbv:700-201111248546 |
| Date | 24 November 2011 |
| Creators | Braams, Simona |
| Contributors | apl. Prof. Dr. Richard Wagner, PD Dr. Thomas Rauen |
| Source Sets | Universität Osnabrück |
| Language | German |
| Detected Language | English |
| Type | doc-type:doctoralThesis |
| Format | application/pdf, application/zip |
| Rights | http://rightsstatements.org/vocab/InC/1.0/ |
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