Connexin and pannexin hemichannels in inflammatory responses of glia and neurons.
Connexin and pannexin hemichannels in inflammatory responses of glia and neurons.
复制标题
DOI：
10.1016/j.brainres.2012.08.042
复制
发表时间：
2012-12-03
期刊：
影响因子：
2.9
通讯作者：
Sáez JC
中科院分区：
文献类型：
--
作者：
Bennett MV;Garré JM;Orellana JA;Bukauskas FF;Nedergaard M;Sáez JC
哺乳动物表达约 20 种不同的连接蛋白（哺乳动物中主要的间隙连接形成蛋白）和 3 种潘联蛋白（内联蛋白的同源物）（无脊椎动物中的主要间隙连接形成蛋白）。在两类间隙连接中，每个通道均由两个半通道形成，每个半通道由每个耦合细胞贡献一个。现在，即使不是普遍的，也普遍认为，当两类半通道不与另一个半通道相对并面向外部环境时，它们可以响应各种生理和病理刺激而打开。连接蛋白（可能还有泛连接蛋白）半通道通透性与细胞间通道的通透性一致，开放的半通道可以是相对较大的分子（例如 ATP 和谷氨酸）的释放位点，这些分子可以充当细胞之间的递质。在这里，我们描述了连接蛋白和泛连接蛋白半通道信号传导发生的三种实验范例。 1) 在脊髓星形胶质细胞培养物中，FGF-1 导致 ATP 释放，ATP 导致 pannexin 半通道打开，然后进一步释放 ATP。随后，几个小时后，连接蛋白半通道也通过未知机制打开。 ATP 的释放似乎通过 P2X7 受体的作用来打开潘联蛋白半通道，然后打开连接蛋白半通道，这两者都是 ATP 可渗透的，从而变得自我维持。 2) 通过在暴露的脊髓上放置小重量来造成脊髓损伤，随后在原发病变周围区域释放 ATP。在星形胶质细胞中 Cx43 被敲低的小鼠中，这种释放大大减少。应用 FGF-1 会在未受伤的脊髓中引起类似的 ATP 释放，而 FGF-1 受体抑制剂 PD173074 可抑制 FGF-1 和损伤诱导的释放。 ATP 释放的减少与炎症的减轻和病变继发性扩张的减少有关。 3) 培养物中的皮质星形胶质细胞因缺氧而变得通透，并且这种效应会因高或低葡萄糖而增强。透化作用的机制是打开 Cx43 半通道，这会导致细胞死亡。激活的小胶质细胞分泌 TNF-α 和 IL-1β，打开星形胶质细胞中的连接蛋白半通道。星形胶质细胞释放 ATP 和谷氨酸，可通过激活神经元板联蛋白半通道杀死共培养中的神经元。这些研究表明两种间隙连接半通道与炎症反应和细胞死亡有关。
Mammals express ~20 different connexins, the main gap junction forming proteins in mammals, and 3 pannexins, homologues of innexins, the main gap junction forming proteins in invertebrates. In both classes of gap junction, each channel is formed by two hemichannels, one contributed by each of the coupled cells. There is now general, if not universal, agreement that hemichannels of both classes can open in response to various physiological and pathological stimuli when they are not apposed to another hemichannels and face the external milieu. Connexin (and likely pannexin) hemichannel permeability is consistent with that of the cell-cell channels and open hemichannels can be a release site for relatively large molecules such as ATP and glutamate, which can serve as transmitters between cells. Here we describe three experimental paradigms in which connexin and pannexin hemichannel signaling occurs. 1) In cultures of spinal astrocytes FGF-1 causes the release of ATP, and ATP causes opening of pannexin hemichannels, which then release further ATP. Subsequently, several hours later, connexin hemichannels are also opened by an unknown mechanism. Release of ATP appears to become self sustaining through action of P2X7 receptors to open pannexin hemichannels and then connexin hemichannels, both of which are ATP permeable. 2) Spinal cord injury by dropping a small weight on the exposed cord is followed by release of ATP in the region surrounding the primary lesion. This release is greatly reduced in a mouse in which Cx43 is knocked down in the astrocytes. Application of FGF-1 causes a similar release of ATP in the uninjured spinal cord, and an inhibitor of the FGF-1 receptor, PD173074, inhibits both FGF-1 and injury-induced release. Reduction in ATP release is associated with reduced inflammation and less secondary expansion of the lesion. 3) Cortical astrocytes in culture are permeabilized by hypoxia, and this effect is increased by high or low glucose. The mechanism of permeabilization is opening of Cx43 hemichannels, which can lead to cell death. Activated microglia secrete TNF-α and IL-1β, which open connexin hemichannels in astrocytes. Astrocytes release ATP and glutamate which can kill neurons in co-culture through activation of neuronal pannexin hemichannels. These studies implicate two kinds of gap junction hemichannel in inflammatory responses and cell death.
登录
查看更多内容
DOI：
10.1073/pnas.012589799
发表时间：
2002-01-08
影响因子：
11.1
作者：
Contreras, JE;Sánchez, HA;Sáez, JC
通讯作者：
Sáez, JC
影响因子：
3.5
作者：
Froger, Nicolas;Orellana, Juan A.;Giaume, Christian
通讯作者：
Giaume, Christian
DOI：
10.1073/pnas.2233464100
发表时间：
2003-11-11
影响因子：
11.1
作者：
Bruzzone, R;Hormuzdi, SG;Monyer, H
通讯作者：
Monyer, H
影响因子：
11.2
作者：
Lai, Charles P. K.;Bechberger, John F.;Naus, Christian C.
通讯作者：
Naus, Christian C.
影响因子：
4.7
作者：
Orellana JA;Froger N;Ezan P;Jiang JX;Bennett MV;Naus CC;Giaume C;Sáez JC
通讯作者：
Sáez JC