Increased thrombospondin-4 after nerve injury mediates disruption of intracellular calcium signaling in primary sensory neurons.
Increased thrombospondin-4 after nerve injury mediates disruption of intracellular calcium signaling in primary sensory neurons.
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DOI：
10.1016/j.neuropharm.2017.02.019
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发表时间：
2017-05-01
影响因子：
4.7
通讯作者：
Pan B
中科院分区：
文献类型：
--
作者：
Guo Y;Zhang Z;Wu HE;Luo ZD;Hogan QH;Pan B
痛性神经损伤通过提高质膜钙-ATPase(PMCA)功能和抑制肌浆网钙-ATPase(SERCA)功能，从而干扰初级感觉神经元的钙信号传导，从而减少内质网(ER)的钙储存并刺激钙储存操作(SOCE)。痛性神经损伤后升高的细胞外基质糖蛋白-4(TSP4)通过高电压激活的Ca~(2+)通道降低背根神经节神经元的钙电流(ICa)，通过低电压激活的Ca~(2+)通道增加ICa，与神经损伤的作用类似。因此，我们研究了TSP4是否在损伤诱导的细胞内钙信号中断中发挥关键作用。我们发现，TSP4增加PMCA活性，抑制SERCA，耗尽内质网钙库，促进钙库操作的钙内流。TSP4基因敲除小鼠损伤后SERCA和PMCA功能改变明显减轻。在电压门控钙通道α2δ1亚单位(Cavα2δ1)条件性基因敲除小鼠中，TSP4对细胞内钙信号的影响是减弱的，并且也是蛋白激酶C信号依赖的。这些结果提示，TSP4的升高可能通过与Cav-α-2-δ-1及随后的PKC信号通路相互作用而干扰细胞内钙信号，从而参与神经损伤后慢性疼痛的发病机制。控制TSP4介导的外周感觉神经元细胞内钙信号可能是神经病理性疼痛止痛药物开发的一个靶点。
Painful nerve injury disrupts Ca2+ signaling in primary sensory neurons by elevating plasma membrane Ca2+-ATPase (PMCA) function and depressing sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) function, which decreases endoplasmic reticulum (ER) Ca2+ stores and stimulates store-operated Ca2+ entry (SOCE). The extracellular matrix glycoprotein thrombospondin-4 (TSP4), which is increased after painful nerve injury, decreases Ca2+ current (ICa) through high-voltage–activated Ca2+ channels and increases ICa through low-voltage–activated Ca2+ channels in dorsal root ganglion neurons, which are events similar to the effect of nerve injury. We therefore examined whether TSP4 plays a critical role in injury-induced disruption of intracellular Ca2+ signaling. We found that TSP4 increases PMCA activity, inhibits SERCA, depletes ER Ca2+ stores, and enhances store-operated Ca2+ influx. Injury-induced changes of SERCA and PMCA function are attenuated in TSP4 knock-out mice. Effects of TSP4 on intracellular Ca2+ signaling are attenuated in voltage-gated Ca2+ channel α2δ1 subunit (Cavα2δ1) conditional knock-out mice and are also Protein Kinase C (PKC) signaling dependent. These findings suggest that TSP4 elevation may contribute to the pathogenesis of chronic pain following nerve injury by disrupting intracellular Ca2+ signaling via interacting with the Cavα2δ1 and the subsequent PKC signaling pathway. Controlling TSP4 mediated intracellular Ca2+ signaling in peripheral sensory neurons may be a target for analgesic drug development for neuropathic pain.