Laboratory of Neuropharmacology and Neurotoxicology, Shanghai University, China.
Protein Cell. 2011 Jun;2(6):437-44. doi: 10.1007/s13238-011-1064-8. Epub 2011 Jul 12.
Diverse subtypes of voltage-gated sodium channels (VGSCs) have been found throughout tissues of the brain, muscles and the heart. Neurotoxins extracted from the venom of the Asian scorpion Buthus martensi Karsch (BmK) act as sodium channel-specific modulators and have therefore been widely used to study VGSCs. α-type neurotoxins, named BmK I, BmK αIV and BmK abT, bind to receptor site-3 on VGSCs and can strongly prolong the inactivation phase of VGSCs. In contrast, β-type neurotoxins, named BmK AS, BmK AS-1, BmK IT and BmK IT2, occupy receptor site-4 on VGSCs and can suppress peak currents and hyperpolarize the activation kinetics of sodium channels. Accumulating evidence from binding assays of scorpion neurotoxins on VGSCs, however, indicate that pharmacological sensitivity of VGSC subtypes to different modulators is much more complex than that suggested by the simple α-type and β-type neurotoxin distinction. Exploring the mechanisms of possible dynamic interactions between site 3-/4-specific modulators and region- and/or species-specific subtypes of VGSCs would therefore greatly expand our understanding of the physiological and pharmacological properties of diverse VGSCs. In this review, we discuss the pharmacological and structural diversity of VGSCs as revealed by studies exploring the binding properties and cross-competitive binding of site 3- or site 4-specific modulators in VGSC subtypes in synaptosomes from distinct tissues of diverse species.
已在大脑、肌肉和心脏的组织中发现了多种电压门控钠离子通道 (VGSC) 亚型。从亚洲蝎子 Buthus martensi Karsch（BmK）毒液中提取的神经毒素作为钠离子通道特异性调节剂，已被广泛用于研究 VGSCs。α 型神经毒素，命名为 BmK I、BmK αIV 和 BmK abT，与 VGSCs 的受体部位 3 结合，并能强烈延长 VGSCs 的失活阶段。相比之下，β 型神经毒素，命名为 BmK AS、BmK AS-1、BmK IT 和 BmK IT2，占据 VGSCs 的受体部位 4，并能抑制峰电流并使钠通道的激活动力学超极化。然而，来自 scorpion 神经毒素与 VGSCs 结合测定的累积证据表明，VGSC 亚型对不同调节剂的药理敏感性比简单的 α 型和 β 型神经毒素区分所暗示的要复杂得多。因此，探索 3/4 位特异性调节剂与区域和/或物种特异性 VGSC 亚型之间可能的动态相互作用的机制，将极大地扩展我们对不同 VGSCs 的生理和药理特性的理解。在这篇综述中，我们讨论了通过研究突触体中不同组织来源的 VGSC 亚型的 3 位或 4 位特异性调节剂的结合特性和交叉竞争结合来揭示的 VGSCs 的药理学和结构多样性。
