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The Journal of biological chemistry v.292 no.4, 2017년, pp.1160 - 1177   SCI SCIE
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Endosomal Phosphatidylinositol 3-Phosphate Promotes Gephyrin Clustering and GABAergic Neurotransmission at Inhibitory Postsynapses

Papadopoulos, Theofilos (From the Department of Molecular Biology, Center of Biochemistry and Molecular Cell Biology, Universitatsmedizin Gottingen, Humboldtallee 23, 37073 Gottingen, Germany, ); Rhee, Hong Jun ( the Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075 Gottingen, Germany, ); Subramanian, Devaraj ( the European Molecular Biology Laboratory (EMBL), Cell Biology and Biophysics Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany, ); Paraskevopoulou, Foteini ( From the Department of Molecular Biology, Center of Biochemistry and Molecular Cell Biology, Universitatsmedizin Gottingen, Humboldtallee 23, 37073 Gottingen, Germany, ); Mueller, Rainer ( the European Molecular Biology Laboratory (EMBL), Cell Biology and Biophysics Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany, ); Schultz, Carsten ( the European Molecular Biology Laboratory (EMBL), Cell Biology and Biophysics Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany, ); Brose, Nils ( the Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075 Gott ); Rhee, Jeong-Seop ( ); Betz, Heinrich ( );
  • 초록  

    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 GABA A 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 GABA A receptors to developing inhibitory postsynapses and thus the formation of postsynaptic membrane specializations.


  • 주제어

    GABA receptor .   inositol phospholipid .   phosphatidylinositol phosphatase .   synapse .   vesicles.  

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