ATP and glutamate released via astroglial connexin 43 hemichannels mediate neuronal death through activation of pannexin 1 hemichannels.
ATP and glutamate released via astroglial connexin 43 hemichannels mediate neuronal death through activation of pannexin 1 hemichannels.
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DOI：
10.1111/j.1471-4159.2011.07210.x
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发表时间：
2011-09
影响因子：
4.7
通讯作者：
Sáez JC
中科院分区：
文献类型：
--
作者：
Orellana JA;Froger N;Ezan P;Jiang JX;Bennett MV;Naus CC;Giaume C;Sáez JC
炎症有助于缺血性脑、糖尿病和阿尔茨海默病的神经退行性变。这种炎症反应的参与者包括小胶质细胞和星形胶质细胞的激活。我们研究了淀粉样蛋白-β肽（Aβ）处理的小胶质细胞对高糖缺氧下星形胶质细胞半通道活性的影响。高糖缺氧3小时后的再氧化诱导星形胶质细胞瞬间通透性和通过Cx43通道的细胞间通讯减少。这两种反应在先前暴露于a β处理的小胶质细胞（CM-Aβ）的条件培养基中24小时的星形胶质细胞中更大，持续时间更长。cm - a - β的作用被TNF-α和IL-1β模拟，并通过可溶性受体中和TNF-α和受体拮抗剂中和IL-1β来消除。星形胶质细胞在基础条件下保护神经元免受缺氧，但暴露于CM-Aβ使它们对遭受亚致死缺氧/再氧化事件的神经元具有毒性，揭示了损伤的加性性质。星形胶质细胞暴露于CM-Aβ后，通过星形胶质细胞Cx43半通道释放的ATP和谷氨酸激活神经元泛联蛋白1 （Panx1）半通道，从而诱导皮质神经元的通透性。与此一致的是，抑制NMDA或P2X受体只能部分降低神经元Panx1半通道的激活和神经元死亡率，但同时抑制这两种受体完全阻止了神经毒性反应。因此，我们认为ATP和谷氨酸触发的体外毒性在神经元Panx1半通道的激活中收敛。因此，我们提出，阻断发炎神经系统中星形胶质细胞和/或神经元表达的半通道可能是减少神经元损失的一种新颖的替代策略。
Inflammation contributes to neurodegeneration in post-ischemic brain, diabetes, and Alzheimer’s disease. Participants to this inflammatory response include activation of microglia and astrocytes. We studied the role of microglia treated with amyloid-β peptide (Aβ) on hemichannel activity of astrocytes subjected to hypoxia in high glucose. Reoxygenation after 3 h hypoxia in high glucose induced transient astroglial permeabilization and reduction in intercellular communication via Cx43 based channels. Both responses were greater and longer lasting in astrocytes previously exposed for 24 h to conditioned medium from Aβ-treated microglia (CM-Aβ). The effects of CM-Aβ were mimicked by TNF-α and IL-1β and were abrogated by neutralizing TNF-α with soluble receptor and IL-1β with a receptor antagonist. Astrocytes under basal conditions protected neurons against hypoxia, but exposure to CM-Aβ made them toxic to neurons subjected to a sub-lethal hypoxia/reoxygenation episode, revealing the additive nature of the insults. Astrocytes exposed to CM-Aβ induce permeabilization of cortical neurons through activation of neuronal pannexin 1 (Panx1) hemichannels by ATP and glutamate released through astroglial Cx43 hemichannels. In agreement, inhibition of NMDA or P2X receptors only partially reduced the activation of neuronal Panx1 hemichannels and neuronal mortality but simultaneous inhibition of both receptors completely prevented the neurotoxic response. Therefore, we suggest that exitotoxicity triggered by ATP and glutamate converges in activation of neuronal Panx1 hemichannels. Thus, we propose that blocking hemichannels expressed by astrocytes and/or neurons in the inflamed nervous system could represent a novel and alternative strategy to reduce neuronal loss.
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影响因子：
--
作者：
Evans, W. Howard;Leybaert, Luc
通讯作者：
Leybaert, Luc
DOI：
10.1097/01.wcb.0000048519.34839.97
发表时间：
2003-03-01
影响因子：
6.3
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Giaume, Christian
影响因子：
3.3
作者：
Mei, X.;Ezan, P.;Koulakoff, A.
通讯作者：
Koulakoff, A.
影响因子：
--
作者：
Kagansky, N;Levy, S;Knobler, H
通讯作者：
Knobler, H