Molecular mechanisms of lipoic acid modulation of T-type calcium channels in pain pathway.
Molecular mechanisms of lipoic acid modulation of T-type calcium channels in pain pathway.
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DOI：
10.1523/jneurosci.5803-08.2009
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发表时间：
2009-07-29
期刊：
影响因子：
--
通讯作者：
Todorovic SM
中科院分区：
文献类型：
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作者：
Lee WY;Orestes P;Latham J;Naik AK;Nelson MT;Vitko I;Perez-Reyes E;Jevtovic-Todorovic V;Todorovic SM
α-硫辛酸（1,2-二硫烷-3-戊酸；硫辛酸）是一种用于治疗人类疼痛疾病的内源性化合物，但其镇痛作用机制尚不清楚。在这里，我们发现硫辛酸选择性抑制天然 CaV3.2 T 型钙电流（T 电流）并减少急性分离的大鼠感觉神经元中 T 通道依赖性细胞兴奋性。将硫辛酸局部注射到体内疼痛感觉神经元（伤害感受器）的外周感受野中，会降低野生型小鼠对有害热和机械刺激的敏感性，但不会降低 CaV3.2 敲除小鼠的敏感性。随后的分子研究表明，硫辛酸通过氧化通道细胞质面上的特定硫醇残基，抑制人胚肾 293 细胞中异源表达的重组 CaV3.2 通道。这项研究首次提供了伤害性离子通道调节的机制证明，这可能有助于硫辛酸在体内的镇痛特性。
α-Lipoic acid (1,2-dithiolane-3-pentanoic acid; lipoic acid) is an endogenous compound used to treat pain disorders in humans, but its mechanisms of analgesic action are not well understood. Here we show that lipoic acid selectively inhibited native CaV3.2 T-type calcium currents (T-currents) and diminished T-channel-dependent cellular excitability in acutely isolated rat sensory neurons. Lipoic acid locally injected into peripheral receptive fields of pain-sensing sensory neurons (nociceptors) in vivo decreased sensitivity to noxious thermal and mechanical stimuli in wild-type but not CaV3.2 knockout mice. Ensuing molecular studies demonstrated that lipoic acid inhibited recombinant CaV3.2 channels heterologously expressed in human embryonic kidney 293 cells by oxidating specific thiol residues on the cytoplasmic face of the channel. This study provides the first mechanistic demonstration of a nociceptive ion channel modulation that may contribute to the documented analgesic properties of lipoic acid in vivo.