Dihydropyridine block of voltage-dependent K+ currents in rat dorsal root ganglion neurons.
Dihydropyridine block of voltage-dependent K+ currents in rat dorsal root ganglion neurons.
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DOI：
10.1016/j.neuroscience.2009.03.012
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发表时间：
2009-06-16
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影响因子：
3.3
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中科院分区：
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二氢吡啶类硝苯地平、尼莫地平和 Bay K 8644 被广泛用作药理学工具，用于评估 L 型电压门控 Ca2+ 通道对各种神经元过程（包括突触传递、兴奋性和第二信使信号传导）的贡献。尽管心脏组织和异源表达系统的证据表明这些化合物可阻断多个电压门控 K+ (Kv) 通道，但它们仍用于神经元制剂中。因为这些化合物已被用来评估 L 型 Ca2+ 通道对背根神经节 (DRG) 神经元中几个不同过程的相对贡献，并且因为 DRG 神经元中存在其他神经元群体中存在的相对广泛的 Kv 通道，我们确定了二氢吡啶阻断这些神经元中 Kv 电流的程度。标准全细胞膜片钳技术用于研究急性分离的成年大鼠 DRG 神经元。测试的所有三种二氢吡啶均阻断 DRG 神经元中的 Kv 电流；硝苯地平和尼莫地平诱导持续 Kv 电流阻断的 IC50 值分别为 14.5 μM 和 6.6 μM。 10 μM 硝苯地平、尼莫地平和 Bay K 8644 的持续电流阻滞程度分别为 44 ± 1.6%、60 ± 2% 和 56 ± 2.9%。当前块既不被 4-氨基吡啶 (5 mM) 也不被四乙铵 (135 mM) 封闭。二氢吡啶诱导的 Kv 电流阻断与电流激活或失活的电压依赖性、失活恢复或电压依赖性阻断的变化无关。然而，二氢吡啶诱导的阻断存在很小的使用依赖性。我们的结果表明，DRG 神经元中的几种类型的 Kv 通道被阻断的机制不同于心肌细胞中 Kv 通道的潜在阻断机制。重要的是，我们的结果表明，如果研究人员希望探索 L 型 Ca2+ 通道对神经元功能的贡献，他们应该考虑使用二氢吡啶以外的替代策略来操纵这些通道。
The dihydropyridines nifedipine, nimodipine and Bay K 8644 are widely used as pharmacological tools to assess the contribution of L-type voltage-gated Ca2+ channels to a variety of neuronal processes including synaptic transmission, excitability and second messenger signaling. These compounds are still used in neuronal preparations despite evidence from cardiac tissue and heterologous expression systems that they block several voltage-gated K+ (Kv) channels. Both because these compounds have been used to assess the relative contribution of L-type Ca2+ channels to several different processes in dorsal root ganglion (DRG) neurons and because a relatively wide variety of Kv channels present in other neuronal populations are present in DRG neurons, we determined the extent to which dihydropyridines block Kv currents in these neurons. Standard whole cell patch clamp techniques were used to study acutely disassociated adult rat DRG neurons. All three dihydropyridines tested blocked Kv currents in DRG neurons; IC50 values for nifedipine and nimodipine-induce block of sustained Kv currents were 14.5 μM and 6.6 μM, respectively. The magnitude of sustained current block was 44 ± 1.6%, 60 ± 2%, and 56 ± 2.9% with 10 μM nifedipine, nimodipine and Bay K 8644, respectively. Current block was occluded by neither 4-aminopyridine (5 mM) nor tetraethylamonium (135 mM). Dihydropyridine-induced block of Kv currents was not associated with a shift in the voltage-dependence of current activation or inactivation, the recovery from inactivation, or voltage dependent block. However, there was a small use-dependence to the dihydropyridine-induced block. Our results suggest that several types of Kv channels in DRG neurons are blocked by mechanisms distinct from those underlying block of Kv channels in cardiac myocytes. Importantly, our results suggest that if investigators wish to explore the contribution of L-type Ca2+ channels to neuronal function, they should consider alternative strategies for the manipulation of these channels than the use of dihydropyridines.