PDF(Pubmed)
Abstract：
Multiple studies have demonstrated that acute ethanol consumption alters brain function and cognition. Nevertheless, the mechanisms underlying this phenomenon remain poorly understood. Astrocyte-mediated gliotransmission is crucial for hippocampal plasticity, and recently, the opening of hemichannels has been found to play a relevant role in this process. Hemichannels are plasma membrane channels composed of six connexins or seven pannexins, respectively, that oligomerize around a central pore. They serve as ionic and molecular exchange conduits between the cytoplasm and extracellular milieu, allowing the release of various paracrine substances, such as ATP, D-serine, and glutamate, and the entry of ions and other substances, such as Ca2+ and glucose. The persistent and exacerbated opening of hemichannels has been associated with the pathogenesis and progression of several brain diseases for at least three mechanisms. The uncontrolled activity of these channels could favor the collapse of ionic gradients and osmotic balance, the release of toxic levels of ATP or glutamate, cell swelling and plasma membrane breakdown and intracellular Ca2+ overload. Here, we evaluated whether acute ethanol exposure affects the activity of astrocyte hemichannels and the possible repercussions of this phenomenon on cytoplasmatic Ca2+ signaling and gliotransmitter release. Acute ethanol exposure triggered the rapid activation of connexin43 and pannexin1 hemichannels in astrocytes, as measured by time-lapse recordings of ethidium uptake. This heightened activity derived from a rapid rise in [Ca2+]i linked to extracellular Ca2+ influx and IP3-evoked Ca2+ release from intracellular Ca2+ stores. Relevantly, the acute ethanol-induced activation of hemichannels contributed to a persistent secondary increase in [Ca2+]i. The [Ca2+]i-dependent activation of hemichannels elicited by ethanol caused the increased release of ATP and glutamate in astroglial cultures and brain slices. Our findings offer fresh perspectives on the potential mechanisms behind acute alcohol-induced brain abnormalities and propose targeting connexin43 and pannexin1 hemichannels in astrocytes as a promising avenue to prevent deleterious consequences of alcohol consumption.
摘要：
多项研究表明，急性乙醇消耗会改变大脑功能和认知能力。然而，这一现象背后的机制仍然知之甚少。星形胶质细胞介导的胶质细胞传递对海马可塑性至关重要，最近,半通道的开放已被发现在这一过程中发挥了相关作用。半通道是由六个连接蛋白或七个膜联蛋白组成的质膜通道，分别,在中心孔周围低聚。它们作为细胞质和细胞外环境之间的离子和分子交换管道，允许释放各种旁分泌物质，比如ATP,D-丝氨酸,和谷氨酸，以及离子和其他物质的进入，如Ca2+和葡萄糖。半通道的持续和加剧的开放与至少三种机制的几种脑疾病的发病机理和进展有关。这些通道的不受控制的活动可能有利于离子梯度和渗透平衡的崩溃，释放有毒的ATP或谷氨酸，细胞肿胀和质膜破坏和细胞内Ca2+过载。这里,我们评估了急性乙醇暴露是否会影响星形胶质细胞半通道的活性,以及这种现象对细胞质Ca2+信号传导和胶质细胞分泌的可能影响.急性乙醇暴露引发星形胶质细胞中连接蛋白43和pannexin1半通道的快速激活，通过乙锭摄取的延时记录来测量。这种增强的活性源于[Ca2]i的迅速上升，与细胞外Ca2内流和IP3诱发的Ca2从细胞内Ca2存储中释放有关。相关性,急性乙醇诱导的半通道激活导致[Ca2]i持续增加。乙醇引起的[Ca2]i依赖性半通道激活导致星形胶质培养物和脑切片中ATP和谷氨酸的释放增加。我们的发现为急性酒精诱导的脑异常背后的潜在机制提供了新的观点，并建议靶向星形胶质细胞中的连接蛋白43和pannexin1半通道作为防止饮酒有害后果的有希望的途径。
