n-alcohols inhibit voltage-gated Na+ channels expressed in Xenopus oocytes
n-alcohols inhibit voltage-gated Na+ channels expressed in Xenopus oocytes
复制标题
DOI：
10.1124/jpet.108.138370
复制
发表时间：
2008-07-01
影响因子：
3.5
通讯作者：
Harris, R. Adron
中科院分区：
文献类型：
--
作者：
Horishita, Takafumi;Harris, R. Adron
电压门控钠通道是可兴奋细胞中动作电位的起始和传播所必需的，被称为局部麻醉剂的靶点。此外，挥发性麻醉药对钠通道的抑制也被认为是全身麻醉的一种机制。正醇产生麻醉，其效力随着碳数的增加而增加，直到达到“截止值”。在本研究中，我们研究了一系列正醇对Na(v)1.2亚基的影响，以确定该通道的醇截止值。我们还研究了短链醇（乙醇）和长链醇（辛醇）对Na(v)1.2、Na(v)1.4、Na(v)1.6和Na(v)1.8亚基的影响，并研究了醇对通道动力学的影响。乙醇和辛醇抑制了所有亚基的钠电流，而正醇对Na(v)1.2通道的抑制表明在壬醇处被切断。乙醇和辛醇产生的开放通道阻滞，在Na(v)1.8中比在其他钠通道中更为明显。Na(v)1.2的抑制是由于激活减少和失活增加。这些结果表明，钠通道可能对正醇具有疏水结合位点，并显示了对正醇和吸入麻醉剂的抑制动力学机制的差异。
Voltage-gated sodium channels are essential for the initiation and propagation of action potentials in excitable cells and are known as a target of local anesthetics. In addition, inhibition of sodium channels by volatile anesthetics has been proposed as a mechanism of general anesthesia. The n-alcohols produce anesthesia, and their potency increases with carbon number until a "cut-off" is reached. In this study, we examined effects of a range of n-alcohols on Na(v)1.2 subunits to determine the alcohol cut-off for this channel. We also studied the effect of a short-chain alcohol (ethanol) and a long-chain alcohol (octanol) on Na(v)1.2, Na(v)1.4, Na(v)1.6, and Na(v)1.8 subunits, and we investigated the effects of alcohol on channel kinetics. Ethanol and octanol inhibited sodium currents of all subunits, and the inhibition of the Na(v)1.2 channel by n-alcohols indicated a cut- off at nonanol. Ethanol and octanol produced open-channel block, which was more pronounced for Na(v)1.8 than for the other sodium channels. Inhibition of Na(v)1.2 was due to decreased activation and increased inactivation. These results suggest that sodium channels may have a hydrophobic binding site for n-alcohols and demonstrate the differences in the kinetic mechanisms of inhibition for n-alcohols and inhaled anesthetics.