Cx43 hemichannels and panx1 channels contribute to ethanol-induced astrocyte dysfunction and damage

IF 4.3 2区 生物学 Q1 BIOLOGY
Gonzalo I. Gómez, Tanhia F. Alvear, Daniela A. Roa, Arantza Farias-Pasten, Sergio A. Vergara, Luis A. Mellado, Claudio J. Martinez-Araya, Juan Prieto-Villalobos, Claudia García-Rodríguez, Natalia Sánchez, Juan C. Sáez, Fernando C. Ortíz, Juan A. Orellana
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Abstract

Alcohol, a widely abused drug, significantly diminishes life quality, causing chronic diseases and psychiatric issues, with severe health, societal, and economic repercussions. Previously, we demonstrated that non-voluntary alcohol consumption increases the opening of Cx43 hemichannels and Panx1 channels in astrocytes from adolescent rats. However, whether ethanol directly affects astroglial hemichannels and, if so, how this impacts the function and survival of astrocytes remains to be elucidated. Clinically relevant concentrations of ethanol boost the opening of Cx43 hemichannels and Panx1 channels in mouse cortical astrocytes, resulting in the release of ATP and glutamate. The activation of these large-pore channels is dependent on Toll-like receptor 4, P2X7 receptors, IL-1β and TNF-α signaling, p38 mitogen-activated protein kinase, and inducible nitric oxide (NO) synthase. Notably, the ethanol-induced opening of Cx43 hemichannels and Panx1 channels leads to alterations in cytokine secretion, NO production, gliotransmitter release, and astrocyte reactivity, ultimately impacting survival. Our study reveals a new mechanism by which ethanol impairs astrocyte function, involving the sequential stimulation of inflammatory pathways that further increase the opening of Cx43 hemichannels and Panx1 channels. We hypothesize that targeting astroglial hemichannels could be a promising pharmacological approach to preserve astrocyte function and synaptic plasticity during the progression of various alcohol use disorders.
Cx43 半通道和 panx1 通道有助于乙醇诱导的星形胶质细胞功能障碍和损伤
酒精是一种被广泛滥用的药物,会大大降低生活质量,引发慢性疾病和精神问题,对健康、社会和经济造成严重影响。此前,我们曾证实,非自愿饮酒会增加青少年大鼠星形胶质细胞中 Cx43 半通道和 Panx1 通道的开放。然而,乙醇是否会直接影响星形胶质细胞半通道,如果会,这又会如何影响星形胶质细胞的功能和存活,这些问题仍有待阐明。临床相关浓度的乙醇会促进小鼠皮质星形胶质细胞中 Cx43 半通道和 Panx1 通道的开放,从而导致 ATP 和谷氨酸的释放。这些大孔通道的激活依赖于 Toll 样受体 4、P2X7 受体、IL-1β 和 TNF-α 信号、p38 丝裂原活化蛋白激酶和诱导型一氧化氮(NO)合酶。值得注意的是,乙醇诱导的 Cx43 半通道和 Panx1 通道开放会导致细胞因子分泌、NO 生成、神经胶质递质释放和星形胶质细胞反应性的改变,最终影响存活率。我们的研究揭示了乙醇损害星形胶质细胞功能的新机制,其中涉及炎症通路的连续刺激,而炎症通路会进一步增加 Cx43 半ich通道和 Panx1 通道的开放。我们假设,在各种酒精使用障碍的进展过程中,以星形胶质半通道为靶点可能是保护星形胶质细胞功能和突触可塑性的一种很有前景的药理学方法。
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来源期刊
Biological Research
Biological Research 生物-生物学
CiteScore
10.10
自引率
0.00%
发文量
33
审稿时长
>12 weeks
期刊介绍: Biological Research is an open access, peer-reviewed journal that encompasses diverse fields of experimental biology, such as biochemistry, bioinformatics, biotechnology, cell biology, cancer, chemical biology, developmental biology, evolutionary biology, genetics, genomics, immunology, marine biology, microbiology, molecular biology, neuroscience, plant biology, physiology, stem cell research, structural biology and systems biology.
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