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Cell. 2015 Apr 23;161(3):610-621. doi: 10.1016/j.cell.2015.03.029.

The cellular mechanisms of neuronal swelling underlying cytotoxic edema.

Author information

1
Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
2
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.
3
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
4
Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 2B5, Canada. Electronic address: bmacvicar@brain.ubc.ca.

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.

PMID:
25910210
DOI:
10.1016/j.cell.2015.03.029
[Indexed for MEDLINE]
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