Thrombospondin-4 divergently regulates voltage-gated Ca2+ channel subtypes in sensory neurons after nerve injury.
Thrombospondin-4 divergently regulates voltage-gated Ca2+ channel subtypes in sensory neurons after nerve injury.
复制标题
血小板传播-4在神经损伤后的感觉神经元中调节电源门控的Ca2+通道亚型。
DOI：
10.1097/j.pain.0000000000000612
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发表时间：
2016-09
期刊：
影响因子：
7.4
通讯作者：
Hogan QH
中科院分区：
文献类型：
--
作者：
Pan B;Guo Y;Wu HE;Park J;Trinh VN;Luo ZD;Hogan QH
痛性周围神经损伤后，高电压激活(HVA)钙电流(ICA)的丧失和低电压激活(LVA)钙电流的增加导致感觉神经元兴奋性升高。神经损伤还伴随着细胞外基质糖蛋白TSP4的表达增加，阻断TSP4的功能可以逆转或预防损伤后的行为超敏反应。因此，我们研究了TSP4对背根神经节(DRG)神经元ICA的调节。在足以刺激HVA ICa的去极化过程中，TSP4可同时减少N型和L型ICa以及相关的细胞内钙瞬变。相反，TSP4在低电压去极化后增加ICa和细胞内钙信号，我们证实这是由于ICa通过T型通道引起的。这些作用可被加巴喷丁阻断，加巴喷丁通过靶向α2δ1钙亚基来缓解神经病理性疼痛。TSP4基因敲除小鼠HVA和LVA ICA的损伤改变明显减轻。在脊髓神经结扎的神经病理性疼痛模型中，TSP4的应用不能进一步调节受损的DRG神经元的ICA。综上所述，这些结果提示，周围神经损伤后TSP_4升高可能通过靶向α-2-δ-1钙亚基，降低背根神经节神经元的HVA和增加LVA，从而参与周围感觉系统的超敏反应。控制TSP4在外周感觉神经元的过度表达可能是神经病理性疼痛止痛药物开发的一个靶点。
Loss of high-voltage–activated (HVA) calcium current (ICa) and gain of low-voltage–activated (LVA) ICa after painful peripheral nerve injury cause elevated excitability in sensory neurons. Nerve injury is also accompanied by increased expression of the extracellular matrix glycoprotein thrombospondin-4 (TSP4), and interruption of TSP4 function can reverse or prevent behavioral hypersensitivity following injury. We therefore investigated TSP4 regulation of ICa in dorsal root ganglion (DRG) neurons. During depolarization adequate to stimulate HVA ICa, TSP4 decreases both N- and L-type ICa and the associated intracellular calcium transient. In contrast, TSP4 increases ICa and the intracellular calcium signal following low voltage depolarization, which we confirmed is due to ICa through T-type channels. These effects are blocked by gabapentin, which ameliorates neuropathic pain by targeting the α2δ1 calcium subunit. Injury-induced changes of HVA and LVA ICa are attenuated in TSP4 knockout mice. In the neuropathic pain model of spinal nerve ligation, TSP4 application did not further regulate ICa of injured DRG neurons. Taken together, these findings suggest that elevated TSP4 following peripheral nerve injury may contribute to hypersensitivity of peripheral sensory systems by decreasing HVA and increasing LVA in DRG neurons via targeting the α2δ1 calcium subunit. Controlling TSP4 overexpression in peripheral sensory neurons may be a target for analgesic drug development for neuropathic pain.