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  Endosomal phosphatidylinositol 3-phosphate promotes gephyrin clustering and GABAergic neurotransmission at inhibitory postsynapses

Papadopoulos, T., Rhee, H. J., Subramanian, D., Paraskevopoulou, F., Mueller, R., Schultz, C., et al. (2017). Endosomal phosphatidylinositol 3-phosphate promotes gephyrin clustering and GABAergic neurotransmission at inhibitory postsynapses. The Journal of Biological Chemistry, 292(4), 1160-1177. doi:10.1074/jbc.M116.771592.

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 Creators:
Papadopoulos, Theofilos, Author
Rhee, Hong Jun, Author
Subramanian, Devaraj, Author
Paraskevopoulou, Foteini, Author
Mueller, Rainer, Author
Schultz, Carsten, Author
Brose, Nils, Author
Rhee, Jeong-Seop, Author
Betz, Heinrich1, 2, Author           
Affiliations:
1Department of Biomedical Optics, Max Planck Institute for Medical Research, Max Planck Society, ou_1497699              
2Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, Jahnstrasse 29, 69120 Heidelberg, DE, ou_1497704              

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Free keywords: GABA receptor, inositol phospholipid, phosphatidylinositol phosphatase, synapse, vesicles
 Abstract: The formation of neuronal synapses and the dynamic regulation of their efficacy depend on the proper assembly of the postsynaptic neurotransmitter receptor apparatus. Receptor recruitment to inhibitory GABAergic postsynapses requires the scaffold protein gephyrin and the guanine nucleotide exchange factor collybistin (Cb). In vitro, the pleckstrin homology domain of Cb binds phosphoinositides, specifically phosphatidylinositol 3-phosphate (PI3P). However, whether PI3P is required for inhibitory postsynapse formation is currently unknown. Here, we investigated the role of PI3P at developing GABAergic postsynapses by using a membrane-permeant PI3P derivative, time-lapse confocal imaging, electrophysiology, as well as knockdown and overexpression of PI3P-metabolizing enzymes. Our results provide the first in cellula evidence that PI3P located at early/sorting endosomes regulates the postsynaptic clustering of gephyrin and GABAA receptors and the strength of inhibitory, but not excitatory, postsynapses in cultured hippocampal neurons. In human embryonic kidney 293 cells, stimulation of gephyrin cluster formation by PI3P depends on Cb. We therefore conclude that the endosomal pool of PI3P, generated by the class III phosphatidylinositol 3-kinase, is important for the Cb-mediated recruitment of gephyrin and GABAA receptors to developing inhibitory postsynapses and thus the formation of postsynaptic membrane specializations.

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Language(s): eng - English
 Dates: 2016-12-092017-01-27
 Publication Status: Issued
 Pages: 19
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 Table of Contents: -
 Rev. Type: Peer
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Title: The Journal of Biological Chemistry
  Other : JBC
Source Genre: Journal
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Publ. Info: Baltimore, etc. : American Society for Biochemistry and Molecular Biology [etc.]
Pages: - Volume / Issue: 292 (4) Sequence Number: - Start / End Page: 1160 - 1177 Identifier: ISSN: 0021-9258
CoNE: https://pure.mpg.de/cone/journals/resource/954925410826_1