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首页> 外文期刊>Journal of Neurochemistry: Offical Journal of the International Society for Neurochemistry >ATP and glutamate released via astroglial connexin 43 hemichannels mediate neuronal death through activation of pannexin 1 hemichannels.
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ATP and glutamate released via astroglial connexin 43 hemichannels mediate neuronal death through activation of pannexin 1 hemichannels.

机译：通过星形胶质连接蛋白43半通道释放的ATP和谷氨酸盐通过激活pannexin 1半通道介导神经元死亡。

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摘要

Inflammation contributes to neurodegeneration in post-ischemic brain, diabetes, and Alzheimer's disease. Participants in this inflammatory response include activation of microglia and astrocytes. We studied the role of microglia treated with amyloid-beta peptide (Abeta) on hemichannel activity of astrocytes subjected to hypoxia in high glucose. Reoxygenation after 3 h hypoxia in high glucose induced transient astroglial permeabilization via Cx43 hemichannels and reduction in intercellular communication via Cx43 cell-cell channels. Both responses were greater and longer lasting in astrocytes previously exposed for 24 h to conditioned medium from Abeta-treated microglia (CM-Abeta). The effects of CM-Abeta were mimicked by TNF-alpha and IL-1beta and were abrogated by neutralizing TNF-alpha with soluble receptor and IL-1beta with a receptor antagonist. Astrocytes under basal conditions protected neurons against hypoxia, but exposure to CM-Abeta made them toxic to neurons subjected to a sub-lethal hypoxia/reoxygenation episode, revealing the additive nature of the insults. Astrocytes exposed to CM-Abeta induced 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 responses to ATP and glutamate converge 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 in various pathological states including Alzheimer's disease, diabetes and ischemia.
机译：炎症会导致缺血后脑，糖尿病和阿尔茨海默氏病的神经变性。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（Abeta）处理的小胶质细胞对高糖低氧下星形胶质细胞半通道活性的作用。高糖低氧3小时后的复氧诱导通过Cx43半通道的瞬时星形胶质透化和通过Cx43细胞-细胞通道的细胞间通讯减少。两种反应在先前暴露于Abeta处理的小胶质细胞（CM-Abeta）的条件培养基中24小时的星形胶质细胞中都更大且更持久。 CM-Abeta的作用被TNF-α和IL-1beta所模仿，并且通过用可溶性受体中和TNF-α和与受体拮抗剂中和IL-1beta来消除。在基础条件下的星形胶质细胞可保护神经元免受缺氧，但是暴露于CM-Abeta使其对遭受亚致死性缺氧/复氧事件的神经元具有毒性，从而揭示了这种侮辱的累加性质。星形胶质细胞暴露于CM-Abeta通过ATP和谷氨酸通过星形胶质Cx43半通道释放来激活神经元pannexin 1（Panx1）半通道，从而诱导皮质神经元通透化。一致地，抑制NMDA或P2X受体仅部分降低了神经元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，我们建议对ATP和谷氨酸的反应在神经元Panx1半通道的激活中收敛。因此，我们建议阻断发炎的神经系统中星形胶质细胞和/或神经元表达的半通道可以代表一种新颖的替代策略，以减少各种病理状态（包括阿尔茨海默氏病，糖尿病和局部缺血）的神经元丢失。

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