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培养的小鼠星形胶质细胞内质网钙反应的昼夜节律调节。

Circadian regulation of endoplasmic reticulum calcium response in cultured mouse astrocytes.

机构信息

Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea.

Department of Brain Science, Ajou University School of Medicine, Suwon, Republic of Korea.

出版信息

Elife. 2024 Nov 27;13:RP96357. doi: 10.7554/eLife.96357.

DOI:10.7554/eLife.96357
PMID:39601391
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11602189/
Abstract

The circadian clock, an internal time-keeping system orchestrates 24 hr rhythms in physiology and behavior by regulating rhythmic transcription in cells. Astrocytes, the most abundant glial cells, play crucial roles in CNS functions, but the impact of the circadian clock on astrocyte functions remains largely unexplored. In this study, we identified 412 circadian rhythmic transcripts in cultured mouse cortical astrocytes through RNA sequencing. Gene Ontology analysis indicated that genes involved in Ca homeostasis are under circadian control. Notably, () exhibited robust circadian rhythmicity at both mRNA and protein levels, a rhythm disrupted in astrocytes lacking the circadian transcription factor, BMAL1. HERP regulated endoplasmic reticulum (ER) Ca release by modulating the degradation of inositol 1,4,5-trisphosphate receptors (ITPRs). ATP-stimulated ER Ca release varied with the circadian phase, being more pronounced at subjective night phase, likely due to the rhythmic expression of ITPR2. Correspondingly, ATP-stimulated cytosolic Ca increases were heightened at the subjective night phase. This rhythmic ER Ca response led to circadian phase-dependent variations in the phosphorylation of Connexin 43 (Ser368) and gap junctional communication. Given the role of gap junction channel (GJC) in propagating Ca signals, we suggest that this circadian regulation of ER Ca responses could affect astrocytic modulation of synaptic activity according to the time of day. Overall, our study enhances the understanding of how the circadian clock influences astrocyte function in the CNS, shedding light on their potential role in daily variations of brain activity and health.

摘要

生物钟是一种内部计时系统，通过调节细胞内的节律性转录来协调生理和行为的 24 小时节律。星形胶质细胞是最丰富的神经胶质细胞，在中枢神经系统功能中发挥着关键作用，但生物钟对星形胶质细胞功能的影响在很大程度上仍未得到探索。在这项研究中，我们通过 RNA 测序鉴定了培养的小鼠皮质星形胶质细胞中的 412 个节律性转录本。基因本体分析表明，参与钙稳态的基因受到生物钟的调控。值得注意的是，()在 mRNA 和蛋白质水平上均表现出强烈的节律性，而在缺乏生物钟转录因子 BMAL1 的星形胶质细胞中，这种节律性被破坏。HERP 通过调节肌醇 1,4,5-三磷酸受体 (ITPRs) 的降解来调节内质网 (ER) Ca 释放。ATP 刺激的 ER Ca 释放随生物钟相位而变化，在主观夜间相位更为明显，可能是由于 ITPR2 的节律性表达所致。相应地，ATP 刺激的胞质 Ca 增加在主观夜间相位升高。这种节律性 ER Ca 反应导致缝隙连接蛋白 43 (Ser368) 的磷酸化和缝隙连接通讯的生物钟相位依赖性变化。鉴于缝隙连接通道 (GJC) 在传播 Ca 信号中的作用，我们认为 ER Ca 反应的这种节律性调节可能会根据一天中的时间影响星形胶质细胞对突触活动的调节。总的来说，我们的研究增强了对生物钟如何影响中枢神经系统星形胶质细胞功能的理解，揭示了它们在大脑活动和健康的日常变化中的潜在作用。

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