Altered sodium channel gating as molecular basis for pain: contribution of activation, inactivation, and resurgent currents.
Altered sodium channel gating as molecular basis for pain: contribution of activation, inactivation, and resurgent currents.
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DOI：
10.1007/978-3-642-41588-3_5
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发表时间：
2014-01-01
影响因子：
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通讯作者：
Waxman, Stephen G
中科院分区：
文献类型：
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作者：
Lampert, Angelika;Eberhardt, Mirjam;Waxman, Stephen G
电压门控钠通道的突变，特别是Nav1.7，可引起遗传性红斑性肢痛症、小纤维神经病、阵发性极端疼痛障碍和慢性疼痛不敏感的遗传性疼痛综合征。这些突变的功能分析提供了理解这些疾病模式的潜在病理机制的可能性，也可能有助于解释正常情况下疼痛的分子机制。这些突变分布在整个通道蛋白上，但对每种疼痛综合征都引起类似的变化。在这篇综述中，我们关注它们对钠通道门控的影响，这可能是通过调节（1）构象（影响所有门控特性）;（2）电压敏感电荷的量（主要影响激活）;（3）蛋白质内的相互作用（例如，失活接头的结合）;和（4）与其它蛋白质的相互作用（例如，用于产生再生电流）。了解每种门控模式的分子基础及其对每种疾病类型中细胞兴奋性和伤害感受的影响，可能为开发更特异和有效的治疗工具提供基础。
Mutations in voltage-gated sodium channels, especially Nav1.7, can cause the genetic pain syndromes inherited erythromelalgia, small fiber neuropathy, paroxysmal extreme pain disorder, and chronic insensitivity to pain. Functional analysis of these mutations offers the possibility of understanding the potential pathomechanisms of these disease patterns and also may help to explicate the molecular mechanisms underlying pain in normal conditions. The mutations are distributed over the whole channel protein, but nevertheless induce similar changes for each pain syndrome. In this review we focus on their impact on sodium channel gating, which may be conferred via modulation of (1) conformation (affecting all gating characteristics); (2) the amount of voltage-sensing charges (affecting mainly activation); (3) interaction within the protein (e.g., binding of the inactivation linker); and (4) interaction with other proteins (e.g., for generation of resurgent currents). Understanding the molecular basis for each gating mode and its impact on cellular excitability and nociception in each disease type may provide a basis for development of more specific and effective therapeutic tools.