A potential role for T-type calcium channels in homocysteinemia-induced peripheral neuropathy
A potential role for T-type calcium channels in homocysteinemia-induced peripheral neuropathy
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DOI：
10.1097/j.pain.0000000000001669
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发表时间：
2019-12-01
期刊：
影响因子：
7.4
通讯作者：
Weiss, Norbert
中科院分区：
文献类型：
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作者：
Gaifullina, Aisylu S.;Lazniewska, Joanna;Weiss, Norbert
同型半胱氨酸血症是一种代谢性疾病，其特征是血液中同型半胱氨酸水平异常高，被认为是周围神经病变的危险因素。然而，同型半胱氨酸对外周伤害性感受的毒性作用的细胞机制尚未得到全面研究。在这里，使用实验同型半胱氨酸血症的啮齿动物模型，我们报告同型半胱氨酸和机械异常性疼痛的发展之间的因果关系。同型半胱氨酸血症诱导的机械异常性疼痛被逆转的药理学抑制T型钙通道。此外，我们的体外研究表明，同型半胱氨酸通过促进Ca（v）3.2通道通过蛋白激酶C依赖性信号通路（需要Ca（v）3.2在特定位点的直接磷酸化）再循环回到质膜来增强重组T型钙电流。总之，这些结果揭示了一种未被识别的信号通路，调节T型钙通道的表达，并可能潜在地有助于与同型半胱氨酸血症相关的周围神经病变的发展。
Homocysteinemia is a metabolic condition characterized by abnormally high level of homocysteine in the blood and is considered to be a risk factor for peripheral neuropathy. However, the cellular mechanisms underlying toxic effects of homocysteine on the processing of peripheral nociception have not yet been investigated comprehensively. Here, using a rodent model of experimental homocysteinemia, we report the causal association between homocysteine and the development of mechanical allodynia. Homocysteinemia-induced mechanical allodynia was reversed on pharmacological inhibition of T-type calcium channels. In addition, our in vitro studies indicate that homocysteine enhances recombinant T-type calcium currents by promoting the recycling of Ca(v)3.2 channels back to the plasma membrane through a protein kinase C-dependent signaling pathway that requires the direct phosphorylation of Ca(v)3.2 at specific loci. Altogether, these results reveal an unrecognized signaling pathway that modulates the expression of T-type calcium channels, and may potentially contribute to the development of peripheral neuropathy associated with homocysteinemia.