Junctophilin-4 is essential for signalling at plasma membrane-endoplasmic reticulum junctions in sensory neurons
Junctophilin-4 is essential for signalling at plasma membrane-endoplasmic reticulum junctions in sensory neurons
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DOI：
10.1101/842476
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发表时间：
2019-11
期刊：
影响因子：
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通讯作者：
Alexandra S. Hogea;Shihab S. Shah;F. Jones;Chase M. Carver;Han Hao;Ce Liang;Dongyang Huang;Xiaona Du;N. Gamper
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文献类型：
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作者：
Alexandra S. Hogea;Shihab S. Shah;F. Jones;Chase M. Carver;Han Hao;Ce Liang;Dongyang Huang;Xiaona Du;N. Gamper
内质网和质膜的连接（ER-PM连接）在原核细胞中起着信号中枢的作用。ER-PM连接存在于外周感觉神经元中，是促炎G蛋白偶联受体信号传导和炎性疼痛产生所必需的。然而，ER-PM连接组装和维护的原理，以及它们在感觉神经元炎症信号传导中的作用才刚刚开始出现。在这里，我们发现结膜亲蛋白家族的成员JPH4在大鼠背根神经节（DRG）神经元中大量表达，并且在响应g蛋白诱导的ER Ca2+储存耗尽时，在ER- pm连接处形成储存操作的Ca2+进入（SOCE）复合物是必需的。此外，我们证明了JPH4和ER Ca2+储存在炎症性疼痛维持中的关键作用。事实上，体内DRG中JPH4表达的下调显著减少了炎症介质缓激肽产生的疼痛持续时间。由于内质网为多种炎症介质的兴奋作用提供Ca2+，我们认为JPH4维持的连接Ca2+信号是炎症性疼痛机制的重要因素。
Junctions of endoplasmic reticulum and plasma membrane (ER-PM junctions) serve as signaling hubs in prokaryotic cells. ER-PM junctions are present in peripheral sensory neurons and are necessary for pro-inflammatory G protein coupled receptor signalling and for inflammatory pain generation. Yet, the principles of ER-PM junctions assembly and maintenance, as well as their role in inflammatory signaling in sensory neurons are only beginning to emerge. Here we discovered that a member of the junctophilin family of proteins, JPH4, is abundantly expressed in rat dorsal root ganglion (DRG) neurons and is necessary for the formation of store operated Ca2+ entry (SOCE) complex at the ER-PM junctions in response to the G-protein induced ER Ca2+ store depletion. Furthermore, we demonstrate a key role of the JPH4 and ER Ca2+ stores in the maintenance of inflammatory pain. Indeed, knockdown of JPH4 expression in DRG in vivo significantly reduced the duration of pain produced by inflammatory mediator bradykinin. Since the ER supplies Ca2+ for the excitatory action of multiple inflammatory mediators, we suggest that junctional Ca2+ signalling maintained by JPH4 is an important contributor to the inflammatory pain mechanisms.