Mechanosensory Signaling in Astrocytes.
Mechanosensory Signaling in Astrocytes.
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DOI：
10.1523/jneurosci.1249-20.2020
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发表时间：
2020-12-02
期刊：
影响因子：
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通讯作者：
Gourine AV
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文献类型：
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作者：
Turovsky EA;Braga A;Yu Y;Esteras N;Korsak A;Theparambil SM;Hadjihambi A;Hosford PS;Teschemacher AG;Marina N;Lythgoe MF;Haydon PG;Gourine AV
机械敏感性是星形胶质细胞的一个众所周知的特征，然而，其潜在的机制和功能意义仍然不清楚。有证据表明，星形胶质细胞对脑灌注压的降低非常敏感，并可能起到颅内压力感受器的作用，用于监测脑血流。这项研究调查了脑干星形胶质细胞中的机械感觉信号，因为这些细胞位于心血管控制回路旁边，并介导脑灌注福尔斯下降引起的血压和心率增加。发现大鼠脑干星形胶质细胞中机械刺激诱发的Ca 2+反应可被（1）连接蛋白通道拮抗剂、连接蛋白43（Cx43）阻断肽Gap 26或Cx43基因敲低;（2）TRPV 4通道拮抗剂;（3）ATP的P2 Y1受体拮抗剂;和（4）磷脂酶C或IP 3受体抑制剂阻断。近端连接试验证实星形胶质细胞中TRPV 4和Cx43通道之间存在相互作用。染料负载实验表明，机械刺激增加羧基荧光素渗透膜通道的开放概率。这些数据表明，星形胶质细胞中的机械感受性Ca 2+反应是由TRPV 4和Cx43通道之间的相互作用介导的，导致Cx43介导的ATP释放，ATP通过P2 Y1受体传播/放大Ca 2+信号和从细胞内储存的Ca 2+募集。在星形胶质细胞特异性Cx43基因敲除小鼠中，Cx43缺陷不影响心率对颅内压急性升高的反应幅度。然而，这些动物在不同脑灌注水平下显示较低的心率，支持连接蛋白半通道介导的星形胶质细胞对CNS交感神经控制回路具有兴奋作用的信号分子释放的假设。有证据表明星形胶质细胞可能作为颅内压力感受器发挥功能，在控制体循环和脑循环中发挥重要作用。为了发挥颅内压力感受器的功能，星形胶质细胞必须具有一种特殊的膜机制，使它们对机械刺激非常敏感。这项研究表明，连接蛋白43（Cx43）半通道的开放导致ATP的释放是星形胶质细胞机械感觉Ca 2+反应的关键中枢事件。这种星形胶质细胞机制在心率的自主控制中起着重要作用。这些数据增加了越来越多的证据，表明星形胶质细胞作为CNS代谢环境的多功能监视器，用于检测潜在代谢威胁的条件，如缺氧，高碳酸血症和灌注减少。
Mechanosensitivity is a well-known feature of astrocytes, however, its underlying mechanisms and functional significance remain unclear. There is evidence that astrocytes are acutely sensitive to decreases in cerebral perfusion pressure and may function as intracranial baroreceptors, tuned to monitor brain blood flow. This study investigated the mechanosensory signaling in brainstem astrocytes, as these cells reside alongside the cardiovascular control circuits and mediate increases in blood pressure and heart rate induced by falls in brain perfusion. It was found that mechanical stimulation-evoked Ca2+ responses in astrocytes of the rat brainstem were blocked by (1) antagonists of connexin channels, connexin 43 (Cx43) blocking peptide Gap26, or Cx43 gene knock-down; (2) antagonists of TRPV4 channels; (3) antagonist of P2Y1 receptors for ATP; and (4) inhibitors of phospholipase C or IP3 receptors. Proximity ligation assay demonstrated interaction between TRPV4 and Cx43 channels in astrocytes. Dye loading experiments showed that mechanical stimulation increased open probability of carboxyfluorescein-permeable membrane channels. These data suggest that mechanosensory Ca2+ responses in astrocytes are mediated by interaction between TRPV4 and Cx43 channels, leading to Cx43-mediated release of ATP which propagates/amplifies Ca2+ signals via P2Y1 receptors and Ca2+ recruitment from the intracellular stores. In astrocyte-specific Cx43 knock-out mice the magnitude of heart rate responses to acute increases in intracranial pressure was not affected by Cx43 deficiency. However, these animals displayed lower heart rates at different levels of cerebral perfusion, supporting the hypothesis of connexin hemichannel-mediated release of signaling molecules by astrocytes having an excitatory action on the CNS sympathetic control circuits. SIGNIFICANCE STATEMENT There is evidence suggesting that astrocytes may function as intracranial baroreceptors that play an important role in the control of systemic and cerebral circulation. To function as intracranial baroreceptors, astrocytes must possess a specialized membrane mechanism that makes them exquisitely sensitive to mechanical stimuli. This study shows that opening of connexin 43 (Cx43) hemichannels leading to the release of ATP is the key central event underlying mechanosensory Ca2+ responses in astrocytes. This astroglial mechanism plays an important role in the autonomic control of heart rate. These data add to the growing body of evidence suggesting that astrocytes function as versatile surveyors of the CNS metabolic milieu, tuned to detect conditions of potential metabolic threat, such as hypoxia, hypercapnia, and reduced perfusion.