Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, USA.
Nat Methods. 2012 Feb 19;9(4):396-402. doi: 10.1038/nmeth.1897.
Local anesthetics effectively suppress pain sensation, but most of these compounds act nonselectively, inhibiting activity of all neurons. Moreover, their actions abate slowly, preventing precise spatial and temporal control of nociception. We developed a photoisomerizable molecule, quaternary ammonium-azobenzene-quaternary ammonium (QAQ), that enables rapid and selective optical control of nociception. QAQ is membrane-impermeant and has no effect on most cells, but it infiltrates pain-sensing neurons through endogenous ion channels that are activated by noxious stimuli, primarily TRPV1. After QAQ accumulates intracellularly, it blocks voltage-gated ion channels in the trans form but not the cis form. QAQ enables reversible optical silencing of mouse nociceptive neuron firing without exogenous gene expression and can serve as a light-sensitive analgesic in rats in vivo. Because intracellular QAQ accumulation is a consequence of nociceptive ion-channel activity, QAQ-mediated photosensitization is a platform for understanding signaling mechanisms in acute and chronic pain.
局部麻醉剂能有效抑制痛觉，但这些化合物大多是非选择性的，会抑制所有神经元的活性。此外，它们的作用消退缓慢，无法精确控制伤害感受的空间和时间。我们开发了一种光致可异构化分子，季铵盐-偶氮苯-季铵盐（QAQ），它可以实现快速和选择性的光控伤害感受。QAQ 不能穿透细胞膜，对大多数细胞没有影响，但它可以通过内源性离子通道渗透到痛觉感受神经元中，这些通道主要由 TRPV1 激活。QAQ 积累在细胞内后，它会阻断电压门控离子通道的转态，但不会阻断顺式构象。QAQ 可以实现对小鼠伤害感受神经元放电的可逆光学沉默，而无需外源性基因表达，并且可以作为体内大鼠的光敏感镇痛剂。由于细胞内 QAQ 的积累是伤害感受离子通道活性的结果，因此 QAQ 介导的光致敏作用是理解急性和慢性疼痛信号机制的平台。
Zotero 插件
