SAP102 regulates synaptic AMPAR function through a CNIH-2-dependent mechanism
| Autor: | Emery N. Brown, Xiaobai Ren, Man Ho Wong, Mingna Liu, Kyung Seok Han, Rebecca Shi, Hongik Hwang, Weifeng Xu, Laura D. Lewis |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Scaffold protein Guanylate kinase Physiology Hippocampus AMPA receptor Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Excitatory synapse mental disorders Animals Receptors AMPA CA1 Region Hippocampal Cells Cultured Mechanism (biology) Chemistry Pyramidal Cells musculoskeletal neural and ocular physiology General Neuroscience Miniature Postsynaptic Potentials Neuropeptides Excitatory Postsynaptic Potentials Rats Cell biology 030104 developmental biology nervous system Disks Large Homolog 4 Protein Postsynaptic density psychological phenomena and processes 030217 neurology & neurosurgery Function (biology) Research Article |
| Zdroj: | Journal of Neurophysiology. 120:1578-1586 |
| ISSN: | 1522-1598 0022-3077 |
| DOI: | 10.1152/jn.00731.2017 |
| Popis: | The postsynaptic density (PSD)-95-like, disk-large (DLG) membrane-associated guanylate kinase (PSD/DLG-MAGUK) family of proteins scaffold α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) complexes to the postsynaptic compartment and are postulated to orchestrate activity-dependent modulation of synaptic AMPAR functions. SAP102 is a key member of this family, present from early development, before PSD-95 and PSD-93, and throughout life. Here we investigate the role of SAP102 in synaptic transmission using a cell-restricted molecular replacement strategy, where SAP102 is expressed against the background of acute knockdown of endogenous PSD-95. We show that SAP102 rescues the decrease of AMPAR-mediated evoked excitatory postsynaptic currents (AMPAR eEPSCs) and AMPAR miniature EPSC (AMPAR mEPSC) frequency caused by acute knockdown of PSD-95. Further analysis of the mini events revealed that PSD-95-to-SAP102 replacement but not direct manipulation of PSD-95 increases the AMPAR mEPSC decay time. SAP102-mediated rescue of AMPAR eEPSCs requires AMPAR auxiliary subunit cornichon-2, whereas cornichon-2 knockdown did not affect PSD-95-mediated regulation of AMPAR eEPSC. Combining these observations, our data elucidate that PSD-95 and SAP102 differentially influence basic synaptic properties and synaptic current kinetics potentially via different AMPAR auxiliary subunits. NEW & NOTEWORTHY Synaptic scaffold proteins postsynaptic density (PSD)-95-like, disk-large (DLG) membrane-associated guanylate kinase (PSD-MAGUKs) regulate synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function. However, the functional diversity among different PSD-MAGUKs remains to be categorized. We show that distinct from PSD-95, SAP102 increase the AMPAR synaptic current decay time, and the effect of SAP102 on synaptic AMPAR function requires the AMPAR auxiliary subunit cornichon-2. Our data suggest that PSD-MAGUKs target and modulate different AMPAR complexes to exert specific experience-dependent modification of the excitatory circuit. |
| Databáze: | OpenAIRE |
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