O2-Dependent Protein Internalization Underlies Astrocytic Sensing of Acute Hypoxia by Restricting Multimodal TRPA1 Channel Responses
O2-Dependent Protein Internalization Underlies Astrocytic Sensing of Acute Hypoxia by Restricting Multimodal TRPA1 Channel Responses
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DOI：
10.1016/j.cub.2020.06.047
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发表时间：
2020-09-07
期刊：
影响因子：
9.2
通讯作者：
Mori, Yasuo
中科院分区：
文献类型：
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作者：
Uchiyama, Makoto;Nakao, Akito;Mori, Yasuo
缺氧传感器对调节体内局部氧（O-2）稳态至关重要。这在中枢神经系统内尤其相关，由于高能量需求，中枢神经系统特别容易受到O-2剥夺的影响。在这里，我们揭示了星形胶质细胞通过中枢神经系统内o -2调节的蛋白运输机制发挥的缺氧监测功能。引人注目的是，从面旁呼吸组（pFRG）和后四边形核（RTN）区分离出来的培养小鼠星形胶质细胞能够通过传感器阳离子通道瞬时受体电位（TRP） A1对中度缺氧做出快速反应，但与多模态感觉神经元不同，在常氧环境下，它们对高氧和其他TRPA1激活剂（二氧化碳、亲电试剂和氧化剂）是惰性的。机制上，O-2通过O-2依赖脯氨酸羟基化和E3泛素连接酶NEDD4-1（神经前体细胞表达的发育下调蛋白4）的泛素化抑制TRPA1通道活性。缺氧抑制这一过程，并在质膜上迅速积累TRPA1蛋白，诱导TRPA1介导的Ca2+内流，触发pFRG/RTN星形胶质细胞释放ATP，增强呼吸中枢活动。此外，小鼠脑干-脊髓制备中星形胶质细胞特异性Trpa1的破坏阻碍了缺氧时中枢自主呼吸输出的振幅增强。因此，TRPA1通道与o -2依赖性蛋白易位的可逆偶联允许星形胶质细胞在髓质呼吸中心充当急性缺氧传感器。
Hypoxia sensors are essential for regulating local oxygen (O-2) homeostasis within the body. This is especially pertinent within the CNS, which is particularly vulnerable to O-2 deprivation due to high energetic demand. Here, we reveal hypoxia-monitoring function exerted by astrocytes through an O-2-regulated protein traf-ficking mechanism within the CNS. Strikingly, cultured mouse astrocytes isolated from the parafacial respiratory group (pFRG) and retrotrapezoid nucleus (RTN) region are capable of rapidly responding to moderate hypoxia via the sensor cation channel transient receptor potential (TRP) A1 but, unlike multimodal sensory neurons, are inert to hyperoxia and other TRPA1 activators (carbon dioxide, electrophiles, and oxidants) in normoxia. Mechanistically, O-2 suppresses TRPA1 channel activity by protein internalization via O-2-depen-dent proline hydroxylation and subsequent ubiquitination by an E3 ubiquitin ligase, NEDD4-1 (neural precur-sor cell-expressed developmentally down-regulated protein 4). Hypoxia inhibits this process and instantly accumulates TRPA1 proteins at the plasma membrane, inducing TRPA1-mediated Ca2+ influx that triggers ATP release from pFRG/RTN astrocytes, potentiating respiratory center activity. Furthermore, astrocyte-specific Trpa1 disruption in a mouse brainstem-spinal cord preparation impedes the amplitude augmenta-tion of the central autonomic respiratory output during hypoxia. Thus, reversible coupling of the TRPA1 chan-nels with O-2-dependent protein translocation allows astrocytes to act as acute hypoxia sensors in the medullary respiratory center.