Kv1.1 channels of dorsal root ganglion neurons are inhibited by n-butyl-p-aminobenzoate, a promising anesthetic for the treatment of chronic pain
Kv1.1 channels of dorsal root ganglion neurons are inhibited by n-butyl-p-aminobenzoate, a promising anesthetic for the treatment of chronic pain
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DOI：
10.1124/jpet.102.042135
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发表时间：
2003-02-01
影响因子：
3.5
通讯作者：
Van den Berg, RJ
中科院分区：
文献类型：
--
作者：
Beekwilder, JP;O'Leary, ME;Van den Berg, RJ
本研究应用膜片钳技术观察了局麻药对氨基苯甲酸丁酯（BAB）对培养的背根神经节（DRG）神经元延迟整流钾电流的影响。小DRG神经元的大部分K+电流在去极化电压下快速激活和缓慢失活。BAB抑制这些神经元的全细胞K+电流，IC 50值为228 μ M。Dendrotoxin K（DTXK）是Kv1.1的特异性抑制剂，在+20 mV时可使DRG K+电流降低34%，这与包含Kv1.1亚基的通道对延迟整流电流的重要贡献一致。为了进一步研究BAB抑制的机制，我们研究了其对哺乳动物tsA201细胞中异源表达的Kv1.1通道的影响。BAB抑制Kv1.1通道，IC 50值为238 μ M，与天然DRG电流所观察到的相似。BAB加速Kv1.1的开放和关闭，但不改变稳态激活的中点。BAB似乎通过稳定通道的闭合构象来抑制Kv1.1。与Kv β 1亚基的共表达诱导Kv1.1的快速失活并降低BAB敏感性。异源表达的Kv1.1和天然DRG电流的比较表明，Kv β 1亚基不调制DTXK敏感的Kv1.1通道的DRG神经元的门控。这些神经元的延迟整流电流的抑制可能有助于在硬膜外给药BAB期间获得的长时间麻醉。
In this study, we investigated the effects of the local anesthetic n-butyl-p-aminobenzoate (BAB) on the delayed rectifier potassium current of cultured dorsal root ganglion (DRG) neurons using the patch-clamp technique. The majority of the K+ current of small DRG neurons rapidly activates and slowly inactivates at depolarized voltages. BAB inhibited the whole-cell K+ current of these neurons with an IC50 value of 228 muM. Dendrotoxin K (DTXK), a specific inhibitor of Kv1.1, reduced the DRG K+ current at +20 mV by 34%, consistent with an important contribution of channels incorporating the Kv1.1 subunit to the delayed rectifier current. To further investigate the mechanism of BAB inhibition, we examined its effect on Kv1.1 channels heterologously expressed in mammalian tsA201 cells. BAB inhibits the Kv1.1 channels with an IC50 value of 238 muM, similar to what was observed for the native DRG current. BAB accelerates the opening and closing of Kv1.1, but does not alter the midpoint of steady-state activation. BAB seems to inhibit Kv1.1 by stabilizing closed conformations of the channel. Coexpression with the Kvbeta1 subunit induces rapid inactivation and reduces the BAB sensitivity of Kv1.1. Comparison of the heterologously expressed Kv1.1 and native DRG currents indicates that the Kvbeta1 subunit does not modulate the gating of the DTXK-sensitive Kv1.1 channels of DRG neurons. Inhibition of the delayed rectifier current of these neurons may contribute to the long-duration anesthesia attained during the epidural administration of BAB.