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.

journal_name

Cell

journal_title

Cell

authors

Rungta RL,Choi HB,Tyson JR,Malik A,Dissing-Olesen L,Lin PJC,Cain SM,Cullis PR,Snutch TP,MacVicar BA

doi

10.1016/j.cell.2015.03.029

subject

Has Abstract

pub_date

2015-04-23 00:00:00

pages

610-621

issue

3

eissn

0092-8674

issn

1097-4172

pii

S0092-8674(15)00316-5

journal_volume

161

pub_type

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