Patel A J, Lauritzen I, Lazdunski M, Honoré E
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UPR 411, 06560 Valbonne, France.
J Neurosci. 1998 May 1;18(9):3117-23. doi: 10.1523/JNEUROSCI.18-09-03117.1998.
Hypoxia and inhibitors of mitochondrial respiration impair the regulatory volume decrease (RVD) of cerebellar granule neurons after hypotonic swelling. RVD is linked to the opening of volume-regulated anion channels (VRACs). VRACs are outwardly rectifying, inactivate slowly during maintained depolarization, and are permeable to the cellular organic osmolyte taurine. Channel activation requires nonhydrolytic ATP binding and is not modulated by intracellular ADP. VRAC opening is reversibly depressed by hypoxia and by mitochondrial inhibitors such as oligomycin, rotenone, and antimycin A. These results demonstrate that neuronal VRAC activation and swelling are both tightly linked to cellular energy. Moreover, the findings reported in this work may have a particular significance for inherited mitochondrial human diseases, such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), which cause brain swelling and edema.
缺氧和线粒体呼吸抑制剂会损害小脑颗粒神经元在低渗肿胀后的调节性容积减小（RVD）。RVD与容积调节性阴离子通道（VRAC）的开放有关。VRAC向外整流，在持续去极化过程中缓慢失活，并且对细胞内有机渗透剂牛磺酸具有通透性。通道激活需要非水解性ATP结合，且不受细胞内ADP的调节。缺氧以及线粒体抑制剂（如寡霉素、鱼藤酮和抗霉素A）会可逆地抑制VRAC的开放。这些结果表明，神经元VRAC的激活和肿胀都与细胞能量紧密相关。此外，这项工作中报道的发现可能对遗传性线粒体人类疾病具有特殊意义，例如线粒体肌病、脑病、乳酸性酸中毒和卒中样发作（MELAS），这些疾病会导致脑肿胀和水肿。
