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

Vivek Mahadevan, C. Sahara Khademullah, Zahra Dargaei, Jonah Chevrier, Pavel Uvarov, Julian Kwan, Richard D. Bagshaw, Tony Pawson, Andrew Emili, Yves DeKoninck, View ORCID ProfileVictor Anggono, Matti S. Airaksinen, View ORCID ProfileMelanie A. Woodin
doi: https://doi.org/10.1101/142265
Vivek Mahadevan
1Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, Ontario, M5S 3G5, Canada
2Present address: Section on Cellular and Synaptic Physiology, NICHD, Bethesda, Maryland, USA
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C. Sahara Khademullah
1Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, Ontario, M5S 3G5, Canada
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Zahra Dargaei
1Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, Ontario, M5S 3G5, Canada
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Jonah Chevrier
1Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, Ontario, M5S 3G5, Canada
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Pavel Uvarov
3Department of Anatomy, Faculty of Medicine, University of Helsinki, Finland
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Julian Kwan
4Department of Molecular Genetics, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, M5S 3E1, Canada
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Richard D. Bagshaw
5Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada
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Tony Pawson
5Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada
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Andrew Emili
4Department of Molecular Genetics, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, M5S 3E1, Canada
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Yves DeKoninck
6Institut Universitaire en Santé Mentale de Québec, Québec, QC G1J 2G3, Canada; Department of Psychiatry and Neuroscience, Université Laval, Québec, QC, G1V 0A6, Canada
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Victor Anggono
7Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, QLD 4072, Australia
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Matti S. Airaksinen
3Department of Anatomy, Faculty of Medicine, University of Helsinki, Finland
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Melanie A. Woodin
1Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, Ontario, M5S 3G5, Canada
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  • For correspondence: m.woodin@utoronto.ca
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Abstract

KCC2 is a neuron-specific K+-Cl− cotransporter essential for establishing the Cl− gradient required for hyperpolarizing inhibition. KCC2 is highly localized to excitatory synapses where it regulates spine morphogenesis and AMPA receptor confinement. Aberrant KCC2 function contributes to numerous human neurological disorders including epilepsy and neuropathic pain. Using unbiased 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 a diverse set of 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 (SYNDAPIN1). We verified the PACSIN1-KCC2 interaction biochemically and demonstrated that shRNA knockdown of PACSIN1 in hippocampal neurons significantly 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.

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  • ↵§ Deceased August 7, 2013

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Posted May 25, 2017.
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Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition
Vivek Mahadevan, C. Sahara Khademullah, Zahra Dargaei, Jonah Chevrier, Pavel Uvarov, Julian Kwan, Richard D. Bagshaw, Tony Pawson, Andrew Emili, Yves DeKoninck, Victor Anggono, Matti S. Airaksinen, Melanie A. Woodin
bioRxiv 142265; doi: https://doi.org/10.1101/142265
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Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition
Vivek Mahadevan, C. Sahara Khademullah, Zahra Dargaei, Jonah Chevrier, Pavel Uvarov, Julian Kwan, Richard D. Bagshaw, Tony Pawson, Andrew Emili, Yves DeKoninck, Victor Anggono, Matti S. Airaksinen, Melanie A. Woodin
bioRxiv 142265; doi: https://doi.org/10.1101/142265

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