title: Kainate receptors coexist in a functional complex with KCC2 and regulate chloride homeostasis in hippocampal neurons.
abstract: KCC2 is the neuron-specific K+-Cl(-) cotransporter required for maintaining low intracellular Cl(-), which is essential for fast inhibitory synaptic transmission in the mature CNS. Despite the requirement of KCC2 for inhibitory synaptic transmission, understanding of the cellular mechanisms that regulate KCC2 expression and function is rudimentary. We examined KCC2 in its native protein complex in vivo to identify key KCC2-interacting partners that regulate KCC2 function. Using blue native-polyacrylamide gel electrophoresis (BN-PAGE), we determined that native KCC2 exists in a macromolecular complex with kainate-type glutamate receptors (KARs). We found that KAR subunits are required for KCC2 oligomerization and surface expression. In accordance with this finding, acute and chronic genetic deletion of KARs decreased KCC2 function and weakened synaptic inhibition in hippocampal neurons. Our results reveal KARs as regulators of KCC2, significantly advancing our growing understanding of the tight interplay between excitation and inhibition.
authors.affiliation: Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.
authors.forename: Vivek
authors.initials: V
authors.lastname: Mahadevan
authors.affiliation: Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Pressey
authors.affiliation: Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.
authors.forename: Brooke A
authors.initials: BA
authors.lastname: Acton
authors.affiliation: Institute of Biomedicine, Anatomy, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Pavel
authors.initials: P
authors.lastname: Uvarov
authors.affiliation: Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.
authors.forename: Michelle Y
authors.initials: MY
authors.lastname: Huang
authors.affiliation: Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.
authors.forename: Jonah
authors.initials: J
authors.lastname: Chevrier
authors.affiliation: Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Puchalski
authors.affiliation: Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.
authors.forename: Caiwei M
authors.initials: CM
authors.lastname: Li
authors.affiliation: Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada.
authors.forename: Evgueni A
authors.initials: EA
authors.lastname: Ivakine
authors.affiliation: Institute of Biomedicine, Anatomy, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Matti S
authors.initials: MS
authors.lastname: Airaksinen
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Delpire
authors.affiliation: Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada; Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada.
authors.forename: Roderick R
authors.initials: RR
authors.lastname: McInnes
authors.affiliation: Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada. Electronic address: m.woodin@utoronto.ca.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Woodin
mesh_terms: D000818:Animals; D002712:Chlorides / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006706:Homeostasis; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000378:metabolism*; D027981:Symporters / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D002712:Chlorides; D018092:Kainic Acid Receptors; D027981:Symporters; D000096922:K Cl- Cotransporters