The Fabry disease-associated lipid Lyso-Gb3 enhances voltage-gated calcium currents in sensory neurons and causes pain.
The Fabry disease-associated lipid Lyso-Gb3 enhances voltage-gated calcium currents in sensory neurons and causes pain.
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DOI：
10.1016/j.neulet.2015.01.084
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发表时间：
2015-05-06
影响因子：
2.5
通讯作者：
Wood JN
中科院分区：
文献类型：
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作者：
Choi L;Vernon J;Kopach O;Minett MS;Mills K;Clayton PT;Meert T;Wood JN
Gb 3和Lyso-Gb 3是法布里病中积累的血浆脂质，可引起小鼠的机械性异常性疼痛。Lyso-Gb 3升高感觉神经元中的细胞内钙水平。Lyso-Gb 3增强小直径DRG神经元的电压依赖性钙电流溶血-Gb 3对感觉神经元的直接作用可能有助于Fabry病的疼痛。法布里病是一种X-连锁溶酶体贮积症，其特征在于鞘糖脂的积聚，并伴有临床表现，如心脏疾病、肾衰竭、疼痛和周围神经病变。球三己糖神经鞘氨醇（lyso-Gb 3）是球三己糖神经酰胺（Gb 3）的脱酰形式，已成为法布里病的标志物。我们研究了Gb 3、lyso-Gb 3和疼痛之间的联系。足底施用溶血-Gb 3或Gb 3在健康小鼠中引起机械性异常性疼痛。在体外应用100 nM lyso-Gb 3可导致10%表达伤害感受器标记物的感觉神经元摄取细胞外钙，在1 μM浓度下可升高至40%，这一浓度可能发生在法布里病患者中。电压依赖性Ca 2+通道的峰值电流密度通过应用1 μM lyso-Gb 3显著增强。这些研究表明，溶血-Gb 3在外周伤害感受神经元的敏化中的直接作用，这可能为治疗法布里病相关疼痛的治疗干预提供机会。
Gb3 and Lyso-Gb3, plasma lipids accumulating in Fabry disease, cause mechanical allodynia in mice. Lyso-Gb3 elevates intracellular calcium level in sensory neurons. Lyso-Gb3 enhances voltage-dependent calcium currents in small-diameter DRG neurons. Direct effects of lyso-Gb3 on sensory neurons may contribute to the pain of Fabry disease. Fabry disease is an X-linked lysosomal storage disorder characterised by accumulation of glycosphingolipids, and accompanied by clinical manifestations, such as cardiac disorders, renal failure, pain and peripheral neuropathy. Globotriaosylsphingosine (lyso-Gb3), a deacylated form of globotriaosylceramide (Gb3), has emerged as a marker of Fabry disease. We investigated the link between Gb3, lyso-Gb3 and pain. Plantar administration of lyso-Gb3 or Gb3 caused mechanical allodynia in healthy mice. In vitro application of 100 nM lyso-Gb3 caused uptake of extracellular calcium in 10% of sensory neurons expressing nociceptor markers, rising to 40% of neurons at 1 μM, a concentration that may occur in Fabry disease patients. Peak current densities of voltage-dependent Ca2+ channels were substantially enhanced by application of 1 μM lyso-Gb3. These studies suggest a direct role for lyso-Gb3 in the sensitisation of peripheral nociceptive neurons that may provide an opportunity for therapeutic intervention in the treatment of Fabry disease-associated pain.
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影响因子：
3.8
作者：
Fabry, H
通讯作者：
Fabry, H
DOI：
10.1073/pnas.94.6.2540
发表时间：
1997-03-18
影响因子：
11.1
作者：
Ohshima, T;Murray, GJ;Kulkarni, AB
通讯作者：
Kulkarni, AB
DOI：
10.1073/pnas.0712309105
发表时间：
2008-02-26
影响因子：
11.1
作者：
Aerts, Johannes M.;Groener, Johanna E.;Poorthuis, Ben J.
通讯作者：
Poorthuis, Ben J.
影响因子：
1.6
作者：
Gupta, S;Ries, M;Schiffmann, R
通讯作者：
Schiffmann, R
影响因子：
16.6
作者：
通讯作者：
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