| dc.contributor.advisor | Brose, Nils Prof. Dr. | |
| dc.contributor.author | Mayer, Simone | |
| dc.date.accessioned | 2014-07-03T10:19:24Z | |
| dc.date.available | 2014-07-03T10:19:24Z | |
| dc.date.issued | 2014-07-03 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0022-5F06-C | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-4584 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Molecular mechanisms of collybistin-dependent gephyrin clustering at inhibitory synapses | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Jahn, Reinhard Prof. Dr. | |
| dc.date.examination | 2014-06-17 | |
| dc.description.abstracteng | Information processing and transmission in neuronal networks in the mammalian brain occurs through intercellular communication between neurons at synapses. Inhibitory synapses play a key role, for example to maintain network homeostasis, and their malfunction results in various neurodevelopmental diseases. At inhibitory postsynapses, neurotransmitter receptors are anchored in apposition to presynaptic neurotransmitter release sites by the scaffold protein gephyrin, whose recruitment is dependent on the presence of collybistin (Cb) in various brain areas, such as the hippocampus. Most Cb isoforms contain three domains, an autoinhibitory src homology 3 (SH3) domain, a Dbl homology (DH) domain, which catalyzes the nucleotide exchange on the small Rho-like GTPase Cdc42, and a pleckstrin homology (PH) domain, which binds to phosphatidylinositol 3-phosphate. The notion of an involvement of Rho family GTPases in the regulation of Cb-dependent gephyrin clustering at synaptic sites is controversial. In this study, we have investigated the involvement of Cdc42 and its closest homolog TC10 in inhibitory postsynapse assembly. We show that both GTPases are able to relieve the autoinhibition of Cb and thereby allow Cb to trigger gephyrin microcluster formation at the plasma membrane in non-neuronal cells. This TC10-triggered Cb-dependent gephyrin microcluster formation requires GTP-bound TC10 and the ability of Cb to bind to phosphoinositides. While Cb can activate TC10 in cells, this is not essential for gephyrin microcluster formation. Furthermore, we identify two distinct binding sites for TC10 on Cb - a GDP-specific one in the DH domain, and a GTP-specific one in the PH domain. In neurons, overexpression of TC10 in its GTP-bound state increases gephyrin clustering and inhibitory neurotransmission, whereas GDP-TC10 has opposite effects. TC10 is membrane-anchored through prenylation, basic residues, and palmitoylation in its carboxy terminus and the former two are required for TC10-triggered Cb-dependent gephyrin microcluster formation. In conclusion, we provide evidence for a dual role of small Rho family GTPases in Cb-dependent gephyrin clustering. Binding in the GTP-bound state to the PH domain relieves the autoinhibition exerted by the SH3 domain and provides a second membrane anchor to target Cb to specific subcellular compartments. | de |
| dc.contributor.coReferee | Schwappach, Blanche Prof. Dr. | |
| dc.contributor.thirdReferee | Moser, Tobias Prof. Dr. | |
| dc.contributor.thirdReferee | Schlüter, Oliver Dr. Dr. | |
| dc.contributor.thirdReferee | Klopfenstein, Dieter Dr. | |
| dc.subject.eng | Cdc42 | de |
| dc.subject.eng | TC10 / RhoQ | de |
| dc.subject.eng | postsynaptic scaffold | de |
| dc.subject.eng | neuroligin | de |
| dc.subject.eng | synaptogenesis | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0022-5F06-C-7 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 789614316 | |