Nelson Michael T, Woo Jiwan, Kang Ho-Won, Vitko Iuliia, Barrett Paula Q, Perez-Reyes Edward, Lee Jung-Ha, Shin Hee-Sup, Todorovic Slobodan M
Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
J Neurosci. 2007 Aug 1;27(31):8250-60. doi: 10.1523/JNEUROSCI.1800-07.2007.
Recent studies have demonstrated an important role for T-type Ca2+ channels (T-channels) in controlling the excitability of peripheral pain-sensing neurons (nociceptors). However, the molecular mechanisms underlying the functions of T-channels in nociceptors are poorly understood. Here, we demonstrate that reducing agents as well as endogenous metal chelators sensitize C-type dorsal root ganglion nociceptors by chelating Zn2+ ions off specific extracellular histidine residues on Ca(v)3.2 T-channels, thus relieving tonic channel inhibition, enhancing Ca(v)3.2 currents, and lowering the threshold for nociceptor excitability in vitro and in vivo. Collectively, these findings describe a novel mechanism of nociceptor sensitization and firmly establish reducing agents, as well as Zn2+, Zn2+-chelating amino acids, and Zn2+-chelating proteins as endogenous modulators of Ca(v)3.2 and nociceptor excitability.
最近的研究表明，T型Ca2+通道（T通道）在控制外周痛觉感受神经元（伤害感受器）的兴奋性方面发挥着重要作用。然而，伤害感受器中T通道功能的分子机制仍知之甚少。在这里，我们证明还原剂以及内源性金属螯合剂通过螯合Ca(v)3.2 T通道上特定细胞外组氨酸残基的Zn2+离子，使C型背根神经节伤害感受器敏感化，从而缓解通道的紧张性抑制，增强Ca(v)3.2电流，并在体外和体内降低伤害感受器兴奋性的阈值。总的来说，这些发现描述了一种伤害感受器敏感化的新机制，并明确将还原剂以及Zn2+、Zn2+螯合氨基酸和Zn2+螯合蛋白确立为Ca(v)3.2和伤害感受器兴奋性的内源性调节剂。
