Wang Sho-Ya, Wang Ging Kuo
Department of Biology, State University of New York at Albany, Albany, NY 12222, USA.
Cell Signal. 2003 Feb;15(2):151-9. doi: 10.1016/s0898-6568(02)00085-2.
Voltage-gated Na(+) channels are heteromeric membrane glycoproteins responsible for the generation of action potentials. A number of diverse lipid-soluble neurotoxins, such as batrachotoxin, veratridine, aconitine, grayanotoxins, pyrethroid insecticides, brevetoxins and ciguatoxin, target voltage-gated Na(+) channels for their primary actions. These toxins promote Na(+) channel opening, induce depolarization of the resting membrane potential, and thus drastically affect the excitability of nerve, muscle and cardiac tissues. Poisoning by these lipid-soluble neurotoxins causes hyperexcitability of excitable tissues, followed by convulsions, paralysis and death in animals. How these lipid-soluble neurotoxins alter Na(+) channel gating mechanistically remains unknown. Recent mapping of receptor sites within the Na(+) channel protein for these neurotoxins using site-directed mutagenesis has provided important clues on this subject. Paradoxically, the receptor site for batrachotoxin and veratridine on the voltage-gated Na(+) channel alpha-subunit appears to be adjacent to or overlap with that for therapeutic drugs such as local anaesthetics (LAs), antidepressants and anticonvulsants. This article reviews the physiological actions of lipid-soluble neurotoxins on voltage-gated Na(+) channels, their receptor sites on the S6 segments of the Na(+) channel alpha-subunit and a possible linkage between their receptors and the gating function of Na(+) channels.
电压门控性钠通道是异源寡聚体膜糖蛋白，负责动作电位的产生。许多不同的脂溶性神经毒素，如箭毒蛙毒素、藜芦碱、乌头碱、灰藓毒素、拟除虫菊酯类杀虫剂、短裸甲藻毒素和雪卡毒素，其主要作用靶点是电压门控性钠通道。这些毒素促进钠通道开放，诱导静息膜电位去极化，从而极大地影响神经、肌肉和心脏组织的兴奋性。这些脂溶性神经毒素中毒会导致可兴奋组织的过度兴奋，随后动物会出现惊厥、麻痹和死亡。这些脂溶性神经毒素如何从机制上改变钠通道门控仍不清楚。最近利用定点诱变技术对这些神经毒素在钠通道蛋白内的受体位点进行定位，为这一课题提供了重要线索。矛盾的是，电压门控性钠通道α亚基上箭毒蛙毒素和藜芦碱的受体位点似乎与局部麻醉药、抗抑郁药和抗惊厥药等治疗药物的受体位点相邻或重叠。本文综述了脂溶性神经毒素对电压门控性钠通道的生理作用、它们在钠通道α亚基S6片段上的受体位点以及它们的受体与钠通道门控功能之间的可能联系。
