基因在钠通道相关疼痛障碍中发挥作用

Q3 Medicine
Neuroforum Pub Date : 2022-03-24 DOI:10.1515/nf-2021-0035
Jannis Körner, N. Haag, I. Kurth, A. Lampert
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引用次数: 1

摘要

电压门控钠通道对疼痛感知至关重要。这可以通过几种导致慢性疼痛或先天性无痛的人类遗传条件来说明。突变的类型,它对神经元兴奋性的影响以及受影响的钠通道亚型描绘了这种疾病的复杂图景。钠通道的遗传变异可能影响复杂的生物物理门控及其运输,与其他蛋白质的关联以及通道蛋白和功能的更复杂的调节,从而使我们能够探索其失调对人类伤害感觉的微妙但有影响的影响。对这些疼痛障碍的详细了解提供了一个独特的机会来了解痛觉和病理状况(如神经性疼痛)的详细复杂性。随着人们对钠通道变异在神经性疼痛中的重要性的认识不断提高,越来越多的患者进行了基因筛查,有时发现了不明确意义的变异(VUS)。生物信息学工具有助于评估其潜在的致病影响,但需要在细胞系中使用膜片钳实验进行功能研究,以便得出可靠的结论。通常细胞系不足以显示与生理相关的表型,而采用更复杂、时间密集的模型,如诱导多能干细胞(ips细胞)。在详细的细胞遗传和功能背景下,确定每个钠通道VUS的作用仍然是一个挑战。为了奠定如此详细解释的基础,我们需要在单个细胞的基础上建立细胞功能和基因转录的相关性,因为有可能使用Patch-Seq技术。我们对功能和遗传感觉神经元亚型及其在神经性疼痛产生中的作用的了解越详细,个人或群体为基础的治疗就越有针对性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Genetics meets function in sodium channel-related pain disorders
Abstract Voltage-gated sodium channels are crucial for pain perception. This is illustrated by several human genetic conditions that lead to either chronic pain or, vice versa, to congenital painlessness. The type of mutation, its impact on neuron excitability as well as the affected sodium channel subtype delineates a complex picture of the disorders. Genetic variants in sodium channels may affect the complex biophysical gating and also their trafficking, association with other proteins and more complex regulations of the channel protein and function, thus allowing us to explore the subtle but impactful effects of their dysregulation for human nociception. A detailed understanding of these pain disorders provides a unique chance to understand the detailed intricacies of nociception and pathological conditions such as neuropathic pain. With increasing awareness of the importance of sodium channel variants in neuropathic pain, more patients are genetically screened, sometimes identifying variants of unclear significance (VUS). Bioinformatic tools help to assess their potential disease causing impact, but functional studies using patch-clamp experiments in cell lines are needed to allow for reliable conclusions. Often cell lines are not sufficient to show a physiologically relevant phenotype and more complex, time intensive models, such as induced pluripotent stem cells (iPS-cells) are employed. A challenge remains to identify the role of each sodium channel VUS in the context of the detailed cellular genetic and functional context. To lay the grounds for such a detailed interpretation, we need a correlation of cellular function and genetic transcription on a single cell basis, as it is possible with the Patch-Seq technique. The more detailed our knowledge becomes on functional and genetic sensory neurons subtypes and their role in the generation of neuropathic pain, the more targeted the personal or population-based treatment can be.
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来源期刊
Neuroforum
Neuroforum NEUROSCIENCES-
CiteScore
1.70
自引率
0.00%
发文量
30
期刊介绍: Neuroforum publishes invited review articles from all areas in neuroscience. Readership includes besides basic and medical neuroscientists also journalists, practicing physicians, school teachers and students. Neuroforum reports on all topics in neuroscience – from molecules to the neuronal networks, from synapses to bioethics.
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