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在动物模型中,LRRC8A通过抑制脊髓突触的NMDA受体活性来构成性地抑制疼痛过敏

Meichun Deng¹, Shao-Rui Chen¹, Meng-Hua Zhou¹

¹Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Science translational medicine

|October 22, 2025

概括

富含白的重复含有蛋白8A (LRRC8A) 抑制脊髓中的N-甲基-d-酸盐受体 (NMDAR) 活性. 减少LRRC8A导致NMDAR过活和神经病痛,但恢复LRRC8A可以缓解疼痛.

科学领域:

神经科学是一个神经科学.
疼痛研究疼痛研究
分子生物学分子生物学

背景情况:

神经性疼痛涉及放大了由脊髓中的N-甲基-d-阿斯巴酸受体 (NMDAR) 过活性驱动的感知传输.
通常抑制脊柱背角突触NMDAR活性的机制在很大程度上是未知的.
氨酸丰富的重复含有蛋白8A (LRRC8A),体积调节的离子通道的一个组成部分,正在研究其在调节NMDARs中的作用.

研究的目的:

阐明LRRC8A在调节突触NMDAR活动中的作用及其对神经病痛的贡献.
为了研究LRRC8A和NMDAR在脊髓中的相互作用.
评估调节LRRC8A对神经病痛的治疗潜力.

主要方法:

在大鼠背部根 (DRG) 和脊髓神经元中评估了LRRC8A表达.
在老鼠中利用siRNA介导的Lrrc8a淘汰,在小鼠DRG神经元中使用条件的Lrrc8a淘汰.
检查了NMDAR的局部化和活性,进行了共免疫沉以评估LRRC8A-NMDAR相互作用,并在动物模型中测试了Lrrc8a的基因传递.

主要成果:

神经损伤减少了DRG LRRC8A表达,而Lrrc8a操纵导致疼痛过敏,NMDAR对抗剂可以逆转这种情况.
Lrrc8a knockdown/knockout增强了突触NMDARs和脊髓中的活动.
LRRC8A与NMDARs直接相互作用,限制了它们的突触贩运和活动;恢复LRRC8A表达缓解了疼痛.

结论:

LRRC8A与NMDARs有物理相互作用,构成性地限制了它们在脊髓中的突触存在和活性.
减少LRRC8A-NMDAR相互作用导致突触NMDARs的增加,导致过度活跃和神经病痛.
通过调节NMDAR功能,LRRC8A代表了神经性疼痛的潜在治疗标.

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