Inhibition of T-type calcium current in rat thalamocortical neurons by isoflurane.
Inhibition of T-type calcium current in rat thalamocortical neurons by isoflurane.
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DOI：
10.1016/j.neuropharm.2012.03.018
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发表时间：
2012-08
影响因子：
4.7
通讯作者：
Todorovic SM
中科院分区：
文献类型：
--
作者：
Eckle VS;Digruccio MR;Uebele VN;Renger JJ;Todorovic SM
丘脑皮质 (TC) 神经元为哺乳动物体感皮层提供主要的感觉输入。这些细胞活性的降低可能对于全身麻醉药诱导意识丧失和促进睡眠（催眠）的能力至关重要。 T 型电压门控钙电流（T 电流）具有调节 TC 神经元细胞兴奋性的关键功能，之前的研究表明挥发性全身麻醉剂可能会改变这些神经元的兴奋性。使用膜片钳技术，我们研究了异氟烷（一种常见的挥发性麻醉剂）调节大鼠急性脑切片中天然 TC 神经元的孤立 T 电流和 T 电流依赖性兴奋性的机制。在电压钳实验中，我们发现异氟烷强烈抑制 T 电流的峰值幅度，在生理膜电位下产生的 IC50 为 1.1%。随后的生物物理学研究表明，抑制在去极化膜电位下更为突出，通道可用性曲线的超极化变化证明了这一点。在电流钳实验中，我们发现异氟烷降低了低阈值钙尖峰 (LTCS) 的去极化速率，因此在抑制孤立 T 电流的相同浓度下增加了反弹尖峰放电的潜伏期。这种效应可以通过新型选择性 T 通道阻断剂 3,5-二氯-N-[1-(2,2-二甲基-四氢-吡喃-4-基甲基)-4-氟-哌啶-4-基甲基]-苯甲酰胺 (TTA-P2) 进行模拟。相比之下，异氟烷和TTA-P2对静息膜电位和细胞输入电阻的影响最小。我们认为丘脑 T 电流的抑制可能导致异氟烷的某些临床特性。
Thalamocortical (TC) neurons provide the major sensory input to the mammalian somatosensory cortex. Decreased activity of these cells may be pivotal in the ability of general anesthetics to induce loss of consciousness and promote sleep (hypnosis). T-type voltage-gated calcium currents (T-currents) have a key function regulating the cellular excitability of TC neurons and previous studies have indicated that volatile general anesthetics may alter the excitability of these neurons. Using a patch-clamp technique, we investigated the mechanisms whereby isoflurane, a common volatile anesthetic, modulates isolated T-currents and T-current-dependent excitability of native TC neurons in acute brain slices of the rat. In voltage-clamp experiments, we found that isoflurane strongly inhibited peak amplitude of T-current, yielding an IC50 of 1.1% at physiological membrane potentials. Ensuing biophysical studies demonstrated that inhibition was more prominent at depolarized membrane potentials as evidenced by hyperpolarizing shifts in channel availability curves. In current-clamp experiments we found that isoflurane decreased the rate of depolarization of low-threshold-calcium spikes (LTCSs) and consequently increased the latency of rebound spike firing at the same concentrations that inhibited isolated T-currents. This effect was mimicked by a novel selective T-channel blocker 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2). In contrast, isoflurane and TTA-P2 had minimal effect on resting membrane potential and cell input resistance. We propose that depression of thalamic T-currents may contribute to some clinical properties of isoflurane.
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影响因子：
4.7
作者：
Eckle, Veit-Simon;Todorovic, Slobodan M.
通讯作者：
Todorovic, Slobodan M.
影响因子：
5.5
作者：
Joksovic, PM;Bayliss, DA;Todorovic, SM
通讯作者：
Todorovic, SM
DOI：
10.1073/pnas.0408089101
发表时间：
2004-12-28
影响因子：
11.1
作者：
Lee, J;Kim, D;Shin, HS
通讯作者：
Shin, HS
影响因子：
2.9
作者：
Detsch, O;Vahle-Hinz, C;Bromm, B
通讯作者：
Bromm, B
影响因子：
2.5
作者：
HERRINGTON, J;LINGLE, CJ
通讯作者：
LINGLE, CJ