Cell specific regulation of NaV1.7 activity and trafficking in rat nodose ganglia neurons

Q2 Medicine Neurobiology of Pain Pub Date : 2022-08-01 DOI:10.1016/j.ynpai.2022.100109
Santiago I. Loya-López , Paz Duran , Dongzhi Ran , Aida Calderon-Rivera , Kimberly Gomez , Aubin Moutal , Rajesh Khanna
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引用次数: 2

Abstract

The voltage-gated sodium NaV1.7 channel sets the threshold for electrogenesis. Mutations in the gene encoding human NaV1.7 (SCN9A) cause painful neuropathies or pain insensitivity. In dorsal root ganglion (DRG) neurons, activity and trafficking of NaV1.7 are regulated by the auxiliary collapsin response mediator protein 2 (CRMP2). Specifically, preventing addition of a small ubiquitin-like modifier (SUMO), by the E2 SUMO-conjugating enzyme Ubc9, at lysine-374 (K374) of CRMP2 reduces NaV1.7 channel trafficking and activity. We previously identified a small molecule, designated 194, that prevented CRMP2 SUMOylation by Ubc9 to reduce NaV1.7 surface expression and currents, leading to a reduction in spinal nociceptive transmission, and culminating in normalization of mechanical allodynia in models of neuropathic pain. In this study, we investigated whether NaV1.7 control via CRMP2-SUMOylation is conserved in nodose ganglion (NG) neurons. This study was motivated by our desire to develop 194 as a safe, non-opioid substitute for persistent pain, which led us to wonder how 194 would impact NaV1.7 in NG neurons, which are responsible for driving the cough reflex. We found functioning NaV1.7 channels in NG neurons; however, they were resistant to downregulation via either CRMP2 knockdown or pharmacological inhibition of CRMP2 SUMOylation by 194. CRMP2 SUMOylation and interaction with NaV1.7 was consered in NG neurons but the endocytic machinery was deficient in the endocytic adaptor protein Numb. Overexpression of Numb rescued CRMP2-dependent regulation on NaV1.7, rendering NG neurons sensitive to 194. Altogether, these data point at the existence of cell-specific mechanisms regulating NaV1.7 trafficking.

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大鼠结节神经节神经元中NaV1.7活性和运输的细胞特异性调控
电压门控钠通道NaV1.7设置了电生成的阈值。编码人类NaV1.7 (SCN9A)的基因突变导致疼痛性神经病变或疼痛不敏感。在背根神经节(DRG)神经元中,NaV1.7的活性和转运受辅助塌陷反应介质蛋白2 (CRMP2)的调控。具体来说,阻止E2 SUMO偶联酶Ubc9在CRMP2的赖氨酸-374 (K374)上添加一个小的泛素样修饰物(SUMO),可以减少NaV1.7通道的运输和活性。我们之前发现了一个小分子,命名为194,它可以阻止Ubc9对CRMP2的summoylation,从而降低NaV1.7表面表达和电流,导致脊髓伤害性传递减少,最终使神经性疼痛模型中的机械性异常性疼痛正常化。在这项研究中,我们研究了通过CRMP2-SUMOylation控制NaV1.7在结节神经节(NG)神经元中是否保守。这项研究的动机是我们希望开发194作为一种安全的,非阿片类药物替代持续疼痛,这使我们想知道194如何影响NG神经元中的NaV1.7,这是负责驱动咳嗽反射的。我们在NG神经元中发现了NaV1.7通道;然而,通过CRMP2敲低或药理抑制CRMP2 SUMOylation,它们对下调具有抗性。在NG神经元中,CRMP2的sumo化和与NaV1.7的相互作用是保守的,但在内吞适应蛋白Numb中,内吞机制是缺乏的。Numb获救的crmp2依赖性调节对NaV1.7的过度表达,使NG神经元对NaV1.7敏感。总之,这些数据表明存在调节NaV1.7转运的细胞特异性机制。
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来源期刊
Neurobiology of Pain
Neurobiology of Pain Medicine-Anesthesiology and Pain Medicine
CiteScore
4.40
自引率
0.00%
发文量
29
审稿时长
54 days
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