title: The cellular mechanisms of neuronal swelling underlying cytotoxic edema.
abstract: Cytotoxic brain edema triggered by neuronal swelling is the chief cause of mortality following brain trauma and cerebral infarct. Using fluorescence lifetime imaging to analyze contributions of intracellular ionic changes in brain slices, we find that intense Na(+) entry triggers a secondary increase in intracellular Cl(-) that is required for neuronal swelling and death. Pharmacological and siRNA-mediated knockdown screening identified the ion exchanger SLC26A11 unexpectedly acting as a voltage-gated Cl(-) channel that is activated upon neuronal depolarization to membrane potentials lower than -20 mV. Blockade of SLC26A11 activity attenuates both neuronal swelling and cell death. Therefore cytotoxic neuronal edema occurs when sufficient Na(+) influx and depolarization is followed by Cl(-) entry via SLC26A11. The resultant NaCl accumulation causes subsequent neuronal swelling leading to neuronal death. These findings shed light on unique elements of volume control in excitable cells and lay the ground for the development of specific treatments for brain edema.
authors.affiliation: Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Ravi L
authors.initials: RL
authors.lastname: Rungta
authors.affiliation: Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Hyun B
authors.initials: HB
authors.lastname: Choi
authors.affiliation: Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Tyson
authors.affiliation: Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Aqsa
authors.initials: A
authors.lastname: Malik
authors.affiliation: Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Lasse
authors.initials: L
authors.lastname: Dissing-Olesen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Paulo J C
authors.initials: PJC
authors.lastname: Lin
authors.affiliation: Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Cain
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Pieter R
authors.initials: PR
authors.lastname: Cullis
authors.affiliation: Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Terrance P
authors.initials: TP
authors.lastname: Snutch
authors.affiliation: Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 2B5, Canada. Electronic address: bmacvicar@brain.ubc.ca.
authors.forename: Brian A
authors.initials: BA
authors.lastname: MacVicar
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death; D002478:Cells, Cultured; D027963:Chloride-Bicarbonate Antiporters / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D012964:Sodium / Q000378:metabolism; D000076988:Sulfate Transporters
chemical_list: D027963:Chloride-Bicarbonate Antiporters; D026901:Membrane Transport Proteins; C494615:Slc26A4 protein, rat; D000076988:Sulfate Transporters; D012964:Sodium