CRAC channels regulate astrocyte Ca2+ signaling and gliotransmitter release to modulate hippocampal GABAergic transmission
CRAC channels regulate astrocyte Ca2+ signaling and gliotransmitter release to modulate hippocampal GABAergic transmission
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DOI：
10.1126/scisignal.aaw5450
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发表时间：
2019-05-21
影响因子：
7.3
通讯作者：
Prakriya, Murali
中科院分区：
文献类型：
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作者：
Toth, Anna B.;Hori, Kotaro;Prakriya, Murali
星形胶质细胞是脑中主要的胶质细胞亚型，通过Ca 2+控制的信号传导机制介导从代谢支持到胶质递质释放的多种功能。尽管有强烈的兴趣，星形胶质细胞中的Ca2+内流途径仍然不清楚，阻碍了对Ca2+信号传导如何与下游星形胶质细胞介导的效应子功能偶联的机制见解。在这里，我们确定了由Orai 1和STIM 1编码的钙库操作的Ca2+释放激活的Ca2+（CRAC）通道，作为在促代谢嘌呤能和蛋白酶激活受体刺激后驱动星形胶质细胞中持续和振荡Ca2+信号的Ca2+进入的主要途径。使用synaptopHluorin作为光学报告，我们表明，星形胶质细胞CRAC通道的开放刺激囊泡胞吐介导的神经胶质递质，包括ATP的释放。此外，切片电生理记录表明，激活星形胶质细胞的蛋白酶激活受体刺激中间神经元在CA1海马增加抑制性突触后电流CA1锥体细胞。这些结果揭示了CRAC通道作为星形胶质细胞Ca2+信号传导、胶质递质释放和星形胶质细胞介导的CA1锥体神经元紧张性抑制的调节剂的核心作用。
Astrocytes are the major glial subtype in the brain and mediate numerous functions ranging from metabolic support to gliotransmitter release through signaling mechanisms controlled by Ca2+. Despite intense interest, the Ca2+ influx pathways in astrocytes remain obscure, hindering mechanistic insights into how Ca2+ signaling is coupled to downstream astrocyte-mediated effector functions. Here, we identified store-operated Ca2+ release-activated Ca2+ (CRAC) channels encoded by Orai1 and STIM1 as a major route of Ca2+ entry for driving sustained and oscillatory Ca2+ signals in astrocytes after stimulation of metabotropic purinergic and protease-activated receptors. Using synaptopHluorin as an optical reporter, we showed that the opening of astrocyte CRAC channels stimulated vesicular exocytosis to mediate the release of gliotransmitters, including ATP. Furthermore, slice electrophysiological recordings showed that activation of astrocytes by protease-activated receptors stimulated interneurons in the CA1 hippocampus to increase inhibitory postsynaptic currents on CA1 pyramidal cells. These results reveal a central role for CRAC channels as regulators of astrocyte Ca2+ signaling, gliotransmitter release, and astrocyte-mediated tonic inhibition of CA1 pyramidal neurons.