Modulation of brain hemichannels and gap junction channels by pro-inflammatory agents and their possible role in neurodegeneration.
Modulation of brain hemichannels and gap junction channels by pro-inflammatory agents and their possible role in neurodegeneration.
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DOI：
10.1089/ars.2008.2130
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发表时间：
2009-02
影响因子：
6.6
通讯作者：
Sáez JC
中科院分区：
文献类型：
--
作者：
Orellana JA;Sáez PJ;Shoji KF;Schalper KA;Palacios-Prado N;Velarde V;Giaume C;Bennett MV;Sáez JC
在正常的大脑、神经元、星形胶质细胞和少突胶质细胞中，最丰富和最活跃的细胞表达泛连接蛋白和连接蛋白，这是形成膜通道的两个家族的蛋白质亚基。大多数现有证据表明，在哺乳动物中，内源性表达的泛连接蛋白仅形成半通道，而连接蛋白既形成间隙连接通道又形成半通道。虽然间隙连接通道连接接触细胞的细胞质并协调电和代谢活动，但半通道连接细胞内和细胞外区室并作为离子和小分子的扩散途径。急性病理威胁条件下的阈下刺激（例如，细胞死亡的全局缺血阈下）增强神经元Cx36和胶质Cx43半通道活性，有利于ATP的释放和预处理的产生。如果刺激足够有害，小胶质细胞过度激活并释放生物活性分子，增加半通道的活性，减少星形胶质网络中的间隙连接通讯，剥夺神经元的星形细胞保护功能，进一步降低神经元的活力。在一些神经退行性疾病中，由低水平的异常蛋白表达引发的持续胶质激活诱导胶质半通道和间隙连接通道紊乱，类似于由缺血或感染性疾病引发的急性炎症反应。这些变化可能发生在中枢神经系统的不同细胞类型中，并在炎症过程中导致神经退行性变。Antiox。氧化还原信号学报，11(1),369-399。
In normal brain, neurons, astrocytes, and oligodendrocytes, the most abundant and active cells express pannexins and connexins, protein subunits of two families forming membrane channels. Most available evidence indicates that in mammals endogenously expressed pannexins form only hemichannels and connexins form both gap junction channels and hemichannels. Whereas gap junction channels connect the cytoplasm of contacting cells and coordinate electric and metabolic activity, hemichannels communicate the intra- and extracellular compartments and serve as a diffusional pathway for ions and small molecules. A subthreshold stimulation by acute pathological threatening conditions (e.g., global ischemia subthreshold for cell death) enhances neuronal Cx36 and glial Cx43 hemichannel activity, favoring ATP release and generation of preconditioning. If the stimulus is sufficiently deleterious, microglia become overactivated and release bioactive molecules that increase the activity of hemichannels and reduce gap junctional communication in astroglial networks, depriving neurons of astrocytic protective functions, and further reducing neuronal viability. Continuous glial activation triggered by low levels of anomalous proteins expressed in several neurodegenerative diseases induce glial hemichannel and gap junction channel disorders similar to those of acute inflammatory responses triggered by ischemia or infectious diseases. These changes are likely to occur in diverse cell types of the CNS and contribute to neurodegeneration during inflammatory process. Antiox. Redox Signal. 11, 369–399.
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