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Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition
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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640428/ https://www.ncbi.nlm.nih.gov/pubmed/29028184 http://dx.doi.org/10.7554/eLife.28270 |
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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 |
author_facet | 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 |
author_sort | Mahadevan, Vivek |
collection | PubMed |
description | 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 (SYNDAPIN1). We verified the PACSIN1-KCC2 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. |
format | Online Article Text |
id | pubmed-5640428 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-56404282017-10-16 Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition 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 eLife Neuroscience 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 (SYNDAPIN1). We verified the PACSIN1-KCC2 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. eLife Sciences Publications, Ltd 2017-10-13 /pmc/articles/PMC5640428/ /pubmed/29028184 http://dx.doi.org/10.7554/eLife.28270 Text en © 2017, Mahadevan et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Neuroscience 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 Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition |
title | Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition |
title_full | Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition |
title_fullStr | Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition |
title_full_unstemmed | Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition |
title_short | Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition |
title_sort | native kcc2 interactome reveals pacsin1 as a critical regulator of synaptic inhibition |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640428/ https://www.ncbi.nlm.nih.gov/pubmed/29028184 http://dx.doi.org/10.7554/eLife.28270 |
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