Mechanisms and functional significance of inhibition of neuronal T-type calcium channels by isoflurane.
Mechanisms and functional significance of inhibition of neuronal T-type calcium channels by isoflurane.
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DOI：
10.1124/mol.108.051664
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发表时间：
2009-03
影响因子：
3.6
通讯作者：
Todorovic, Slobodan M.
中科院分区：
文献类型：
--
作者：
Orestes, Peihan;Bojadzic, Damir;Chow, Robert M.;Todorovic, Slobodan M.
以前的数据表明，T型钙通道（低电压激活，LVA，T通道）被挥发性麻醉剂强效抑制。虽然已经描述了T通道与许多麻醉剂的相互作用，但这些药物调节通道活性的机制以及这种相互作用的功能后果尚未得到充分研究。在这里，我们使用膜片钳记录，探索一个典型的挥发性麻醉剂，异氟烷（ISO），重组人CaV3.1和CaV3.2亚型的行动。我们还在缺乏CaV3.2的小鼠中进行了麻醉终点的行为测试。在静息通道状态下应用的Iso在临床相关浓度（1个最小肺泡浓度，MAC）下以类似方式阻断通过两种亚型的电流。抑制作用在去极化膜电位（−65 mV vs −100 mV）下更为突出，通道可用性曲线超极化偏移和IC 50值降低2.5倍证明了这一点。Iso以类似的方式减缓了CaV3.1和CaV3.2的失活恢复并增强了失活，但引起了激活曲线的去极化偏移和CaV3.2通道的更大使用依赖性阻断。在行为测试中，CaV3.2敲除（KO）小鼠显示与野生型（WT）同窝出生小鼠相比MAC显著降低。KO和WT小鼠在翻正反射（LORR）丧失方面没有差异，但突变小鼠显示麻醉诱导延迟起效。我们的结论是，状态依赖性抑制T-通道亚型在中枢和外周神经系统可能有助于异氟烷的重要临床效果。
Previous data have indicated that T-type calcium channels (low-voltage activated, LVA, T-channels) are potently inhibited by volatile anesthetics. Although the interactions of T-channels with a number of anesthetics have been described, the mechanisms by which these agents modulate channel activity, and the functional consequences of such interactions, are not well studied. Here, we used patch-clamp recordings to explore the actions of a prototypical volatile anesthetic, isoflurane (Iso), on recombinant human CaV3.1 and CaV3.2 isoforms. We also performed behavioral testing of anesthetic end-points in mice lacking CaV3.2. Iso applied at resting channel states blocked current through both isoforms in a similar manner at clinically relevant concentrations (1 minimum alveolar concentration, MAC). Inhibition was more prominent at depolarized membrane potentials (−65 mV versus −100 mV) as evidenced by hyperpolarizing shifts in channel availability curves and a 2.5-fold decrease in IC50 values. Iso slowed recovery from inactivation and enhanced deactivation in both CaV3.1 and CaV3.2 in a comparable manner, but caused a depolarizing shift in activation curves and greater use-dependent block of CaV3.2 channels. In behavioral tests, CaV3.2 knockout (KO) mice showed significantly decreased MAC in comparison to wild type (WT) littermates. KO and WT mice did not differ in loss of righting reflex (LORR), but mutant mice displayed a delayed onset of anesthetic induction. We conclude that state-dependent inhibition of T-channel isoforms in the central and peripheral nervous system may contribute to isoflurane's important clinical effects.
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影响因子：
8.8
作者：
Camara, AKS;Begic, Z;Bosnjak, ZJ
通讯作者：
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