Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition

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http://hdl.handle.net/10138/228341

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Mahadevan , V , Khademullah , C S , Dargaei , Z , Chevrier , J , Uvarov , P , Kwan , J , Bagshaw , R D , Pawson , T , Emili , A , De Koninck , Y , Anggono , V , Airaksinen , M & Woodin , M A 2017 , ' Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition ' , eLife , vol. 6 , 28270 . https://doi.org/10.7554/eLife.28270

Title: Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition
Author: Mahadevan, Vivek; Khademullah, C. Sahara; Dargaei, Zahra; Chevrier, Jonah; Uvarov, Pavel; Kwan, Julian; Bagshaw, Richard D.; Pawson, Tony; Emili, Andrew; De Koninck, Yves; Anggono, Victor; Airaksinen, Matti; Woodin, Melanie A.
Contributor: University of Helsinki, Medicum
University of Helsinki, Medicum
Date: 2017-10-13
Language: eng
Number of pages: 34
Belongs to series: eLife
ISSN: 2050-084X
URI: http://hdl.handle.net/10138/228341
Abstract: KCC2 is a neuron-specific K+-Cl- cotransporter essential for establishing the Cl- gradient required for hyperpolarizing inhibition in the central nervous system (CNS). KCC2 is highly localized to excitatory synapses where it regulates spine morphogenesis and AMPA receptor confinement. Aberrant KCC2 function contributes to human neurological disorders including epilepsy and neuropathic pain. Using functional proteomics, we identified the KCC2-interactome in the mouse brain to determine KCC2-protein interactions that regulate KCC2 function. Our analysis revealed that KCC2 interacts with diverse proteins, and its most predominant interactors play important roles in postsynaptic receptor recycling. The most abundant KCC2 interactor is a neuronal endocytic regulatory protein termed PACSIN1 (SYNDAPI N1). We verified the PACSIN1KCC2 interaction biochemically and demonstrated that shRNA knockdown of PACSIN1 in hippocampal neurons increases KCC2 expression and hyperpolarizes the reversal potential for Cl-. Overall, our global native-KCC2 interactome and subsequent characterization revealed PACSIN1 as a novel and potent negative regulator of KCC2.
Subject: K-CL COTRANSPORTER
CATION-CHLORIDE COTRANSPORTERS
TANDEM MASS-SPECTRA
HIGH-RESOLUTION PROTEOMICS
AMPA RECEPTOR TRAFFICKING
DATABASE SEARCH TOOL
LONG-TERM DEPRESSION
HIPPOCAMPAL-NEURONS
GABAERGIC INHIBITION
DENDRITIC SPINES
3111 Biomedicine
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