Antagonism of lidocaine inhibition by open-channel blockers that generate resurgent Na current.
Antagonism of lidocaine inhibition by open-channel blockers that generate resurgent Na current.
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DOI：
10.1523/jneurosci.3026-12.2013
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发表时间：
2013-03-13
期刊：
影响因子：
--
通讯作者：
Raman IM
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文献类型：
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作者：
Bant JS;Aman TK;Raman IM
产生复苏电流的Na通道表达细胞内内源性开放通道阻断蛋白，其在去极化时的快速结合和在复极化时的解结合最小化快速和缓慢失活。Na通道还结合外源性化合物，如利多卡因，其功能上稳定失活。与内源性阻断蛋白一样，这些使用依赖性抑制剂在去极化电位下最有效地结合，从而提出了利多卡因样化合物如何影响具有复苏Na电流的神经元的问题。因此，我们记录了利多卡因对小鼠浦肯野神经元（表达天然阻断蛋白）和小鼠海马CA 3锥体神经元（有和无NaVβ4胞质尾肽（β4肽），模拟内源性开放通道阻断）中电压钳位、河豚毒素敏感性Na电流的抑制。为了控制药物暴露期间的通道状态，在特定电压的步骤期间使用快速溶液交换技术应用利多卡因。利多卡因对钠电流的抑制作用可被β4肽或天然阻断蛋白减弱。在无肽CA 3细胞中，用位点3毒素（海葵毒素II）延长通道开放，降低利多卡因抑制;这种作用在很大程度上被开放通道阻滞剂阻断，表明利多卡因结合受到失活的青睐，但被开放通道阻滞剂阻止。在恒定的100 μM利多卡因中，电流钳位浦肯野细胞继续自发放电。类似地，β4肽减少了切片中CA 3神经元中的利多卡因依赖性尖峰抑制。因此，负责复活电流的开放通道阻断蛋白充当利多卡因的天然拮抗剂。因此，具有复苏电流的神经元可能对用作局部麻醉剂、抗惊厥药和抗惊厥药的使用依赖性Na通道抑制剂不太敏感。
Na channels that generate resurgent current express an intracellular endogenous open-channel blocking protein, whose rapid binding upon depolarization and unbinding upon repolarization minimizes fast and slow inactivation. Na channels also bind exogenous compounds, such as lidocaine, which functionally stabilize inactivation. Like the endogenous blocking protein, these use-dependent inhibitors bind most effectively at depolarized potentials, raising the question of how lidocaine-like compounds affect neurons with resurgent Na current. We therefore recorded lidocaine inhibition of voltage-clamped, tetrodotoxin-sensitive Na currents in mouse Purkinje neurons, which express a native blocking protein, and in mouse hippocampal CA3 pyramidal neurons with and without a peptide from the cytoplasmic tail of NaVβ4 (the β4 peptide), which mimics endogenous open-channel block. To control channel states during drug exposure, lidocaine was applied with rapid-solution exchange techniques during steps to specific voltages. Inhibition of Na currents by lidocaine was diminished by either the β4 peptide or the native blocking protein. In peptide-free CA3 cells, prolonging channel opening with a site-3 toxin, anemone toxin II, reduced lidocaine inhibition; this effect was largely occluded by open-channel blockers, suggesting that lidocaine binding is favored by inactivation but prevented by open-channel block. In constant 100 μM lidocaine, current-clamped Purkinje cells continued to fire spontaneously. Similarly, the β4 peptide reduced lidocaine-dependent suppression of spiking in CA3 neurons in slices. Thus, the open-channel blocking protein responsible for resurgent current acts as a natural antagonist of lidocaine. Neurons with resurgent current may therefore be less susceptible to use-dependent Na channel inhibitors used as local anesthetic, antiarrhythmic, and anticonvulsant drugs.