细胞毒性水肿中神经元肿胀的细胞机制。

The cellular mechanisms of neuronal swelling underlying cytotoxic edema.

机构信息

Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 2B5, Canada.

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.

出版信息

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

DOI:10.1016/j.cell.2015.03.029

PMID:25910210

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.

摘要

细胞毒性脑水肿是由神经元肿胀引起的，是脑外伤和脑梗死患者死亡的主要原因。本研究使用荧光寿命成像分析脑切片中细胞内离子变化的贡献，发现强烈的钠离子内流触发了细胞内氯离子的继发性增加，氯离子的增加是神经元肿胀和死亡所必需的。通过药理学和 siRNA 介导的敲低筛选，出乎意料地发现离子交换体 SLC26A11 作为一种电压门控氯离子通道而发挥作用，该通道在神经元去极化至低于-20 mV 的膜电位时被激活。阻断 SLC26A11 的活性可减轻神经元肿胀和细胞死亡。因此，当足够的钠离子内流和去极化后，氯离子通过 SLC26A11 内流，就会发生细胞毒性神经元水肿。由此产生的 NaCl 积累导致随后的神经元肿胀，进而导致神经元死亡。这些发现揭示了兴奋细胞容量控制的独特元素，并为脑水肿的特定治疗方法的发展奠定了基础。