HCN1 channel subunits are a molecular substrate for hypnotic actions of ketamine.
HCN1 channel subunits are a molecular substrate for hypnotic actions of ketamine.
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HCN1 通道亚基是氯胺酮催眠作用的分子底物
DOI：
10.1523/jneurosci.3481-08.2009
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发表时间：
2009-01-21
期刊：
影响因子：
--
通讯作者：
Bayliss DA
中科院分区：
文献类型：
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作者：
Chen X;Shu S;Bayliss DA
氯胺酮具有重要的麻醉、镇痛和精神作用。人们普遍认为，NMDA受体抑制占氯胺酮的行动，但仍然缺乏行为证据来支持这一假设。在这里，我们提出了一种替代的，行为相关的分子底物氯胺酮的麻醉作用：HCN 1起搏器通道，神经元超极化激活的阳离子电流（I h）的基础。氯胺酮在临床相关浓度下引起重组含HCN 1通道和神经元I h的亚基特异性抑制; S-（+）-氯胺酮对通道的抑制作用比外消旋氯胺酮更强，与化合物的麻醉作用一致。在野生型皮质锥体神经元中，但不是HCN 1基因敲除小鼠，氯胺酮诱导膜超极化和增强树突体突触耦合;已知这两种作用促进皮质同步化并支持缓慢的皮质节律，如伴随麻醉诱导的催眠。因此，我们发现氯胺酮引起翻正反射丧失的效力，催眠的行为相关性，在HCN 1基因敲除小鼠中强烈降低。此外，HCN 1基因敲除小鼠对其他两种静脉麻醉药的催眠敏感性与对HCN 1通道的影响相匹配;丙泊酚选择性抑制HCN 1通道，HCN 1基因敲除小鼠对丙泊酚的敏感性降低，而依托咪酯对HCN 1通道没有影响，HCN 1基因缺失不影响依托咪酯的催眠敏感性。这些数据推进HCN 1通道作为氯胺酮的一种新的分子靶点，提供了一个合理的神经元机制，在麻醉诱导的催眠过程中增强皮层同步，并表明HCN 1通道可能有助于氯胺酮的其他无法解释的行动。
Ketamine has important anesthetic, analgesic, and psychotropic actions. It is widely believed that NMDA receptor inhibition accounts for ketamine actions, but there remains a dearth of behavioral evidence to support this hypothesis. Here, we present an alternative, behaviorally relevant molecular substrate for anesthetic effects of ketamine: the HCN1 pacemaker channels that underlie a neuronal hyperpolarization-activated cationic current (I h). Ketamine caused subunit-specific inhibition of recombinant HCN1-containing channels and neuronal I h at clinically relevant concentrations; the channels were more potently inhibited by S-(+)-ketamine than racemic ketamine, consistent with anesthetic actions of the compounds. In cortical pyramidal neurons from wild-type, but not HCN1 knock-out mice, ketamine induced membrane hyperpolarization and enhanced dendritosomatic synaptic coupling; both effects are known to promote cortical synchronization and support slow cortical rhythms, like those accompanying anesthetic-induced hypnosis. Accordingly, we found that the potency for ketamine to provoke a loss-of-righting reflex, a behavioral correlate of hypnosis, was strongly reduced in HCN1 knock-out mice. In addition, hypnotic sensitivity to two other intravenous anesthetics in HCN1 knock-out mice matched effects on HCN1 channels; propofol selectively inhibited HCN1 channels and propofol sensitivity was diminished in HCN1 knock-out mice, whereas etomidate had no effect on HCN1 channels and hypnotic sensitivity to etomidate was unaffected by HCN1 gene deletion. These data advance HCN1 channels as a novel molecular target for ketamine, provide a plausible neuronal mechanism for enhanced cortical synchronization during anesthetic-induced hypnosis and suggest that HCN1 channels might contribute to other unexplained actions of ketamine.