电压门控钠通道β亚基在蜜蜂毒肽诱导的炎性病理性痛中的可塑性及功能

发布时间：2018-02-02 17:55

本文关键词： 电压门控性钠离子通道 VGSC 神经病理性疼痛炎性病理性痛 β亚基蜜蜂毒肽　出处：《第四军医大学》2011年硕士论文　论文类型：学位论文

【摘要】：电压门控性钠离子通道(voltage-gated sodium channel, VGSC)是一个较大的核心结构α亚基和一个至多个辅助性β亚基构成的跨膜蛋白多聚体,其主要功能是维持神经系统、骨骼肌和心肌等可兴奋组织动作电位的产生和传导。其中α亚基是钠通道的功能性单位,决定着钠离子通道的门控特性和电压依赖性,然而β亚基作为钠离子通道的重要组成部分亦发挥着重要的调节作用。它们能够调节钠离子通道在细胞表面的表达、分布、聚集、开放频率以及门控特性。在各种神经病理性疼痛模型中,如坐骨神经分支选择性损伤(spared nerve injury,SNI)模型、慢性压缩性损伤(chronic constriction injury,CCI)模型、脊神经结扎(spinal nerve ligation,SNL)模型,可以观察到β亚基表达及功能的改变参与了外周神经痛敏的形成和维持。在神经病理性疼痛模型中可以发现受损神经元的一系列变化,如Nav1.3和β2或者β3亚基的上调,与此同时,其他钠离子通道α亚基和β亚基则发生下调,而未受损神经元则没有这些变化。河豚毒素不敏感性( tetrodotoxin-resistant, TTX-R)钠通道的电流密度也降低,稳态失活曲线也向去极化移动。在脊神经结扎模型中,受损神经元河豚毒素敏感性( tetrodotoxin-sensitive, TTX-S)钠通道电流密度没有发生变化,而通道复活速度则加快。已知β亚基能够调节Navα亚基的基因以及蛋白表达水平,修饰其生理功能,β2或者β3亚基可能参与调节神经病理性疼痛中Navα亚基的一系列变化,虽然在炎性病理性痛模型中Navα亚基也发生了可塑性变化,但β亚基是否发挥了调控作用尚没有文献报道。本实验主要通过建立炎性病理性痛模型观察β亚基与Navα亚基如Nav1.8或者Nav1.9的可塑性变化。我们发现在完全弗氏佐剂CFA致炎模型和蜜蜂毒肽Melittin模型中,β1-4亚基和Nav1.8和Nav1.9亚基均发生明显上调。而Western-blotting实验和免疫组化实验亦发现β2、β3亚基发生上调。考虑到β亚基的调控作用如Navβ3能够调节Nav1.8的表达,因而阻断β亚基对Navα亚基的调控可能成为临床镇痛的新思路。
[Abstract]:Voltage-gated sodium channel is a voltage-gated sodium channel. VGSCs are a transmembrane protein polymer composed of a large core structure 伪 subunit and one or more auxiliary 尾 subunits. The main function of VGSCs is to maintain the nervous system. The generation and conduction of action potential in excitable tissues such as skeletal muscle and myocardium, in which 伪 subunit is the functional unit of sodium channel, which determines the gated characteristics and voltage dependence of sodium ion channel. However, as an important component of sodium channel, 尾 subunit also plays an important role in regulating the expression, distribution and aggregation of sodium channel on the cell surface. Open frequency and gating characteristics. In various neuropathic pain models, such as sciatic nerve branch selective injury spared nerve injury-SNI model. Chronic constriction injury-induced CCI model. In spinal nerve ligation model, it was observed that the changes of 尾 subunit expression and function were involved in the formation and maintenance of peripheral neuralgia sensitivity. A series of changes in injured neurons, such as the up-regulation of Nav1.3 and 尾 _ 2 or 尾 _ 3 subunits, can be found in neuropathic pain models. Other sodium channel 伪 subunits and 尾 subunits were down-regulated, while no such changes were found in uninjured neurons. Tetrodotoxin insensitivity (tetrodotoxin-resistant). The current density of TTX-R) sodium channel also decreased, and the steady-state inactivation curve also moved toward depolarization, in the spinal nerve ligation model. There was no change in the current density of tetrodotoxin-sensitive (TTX-S) sodium channels in injured neurons. It is known that 尾 subunit can regulate the gene and protein expression of Nav 伪 subunit and modify its physiological function. 尾 2 or 尾 3 subunits may be involved in the regulation of a series of changes in Nav 伪 subunits in neuropathic pain, although the Nav 伪 subunits also have plastic changes in inflammatory pathological pain models. However, whether 尾-subunit plays a regulatory role has not been reported. In this experiment, we observed the plasticity of 尾 subunit and Nav 伪 subunit such as Nav1.8 or Nav1.9 by establishing inflammatory pathological pain model. We found that the inflammatory model was induced by complete Freund's adjuvant CFA. And bee venom peptide Melittin model. 尾 _ 1-4 subunits, Nav1.8 and Nav1.9 subunits were up-regulated, and 尾 _ 2 was also found by Western-blotting assay and immunohistochemistry. The regulation of 尾 3 subunit such as Nav 尾 3 can regulate the expression of Nav1.8, so blocking the regulation of 尾 3 subunit on Nav 伪 subunit may be a new way of clinical analgesia.
【学位授予单位】：第四军医大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R363

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