Mechanisms of inhibition of Cav3.1 T-type calcium current by aliphatic alcohols
Mechanisms of inhibition of Cav3.1 T-type calcium current by aliphatic alcohols
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DOI：
10.1016/j.neuropharm.2010.03.016
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发表时间：
2010-07-01
影响因子：
4.7
通讯作者：
Todorovic, Slobodan M.
中科院分区：
文献类型：
--
作者：
Eckle, Veit-Simon;Todorovic, Slobodan M.
许多脂肪醇调节参与感觉加工的各种离子通道的活性，并且在体内也表现出麻醉能力。尽管已经描述了一种这样的化合物1-辛醇（octanol）与不同的T型钙通道（T通道）的相互作用，但是电流调节的机制及其功能意义还没有得到很好的研究。应用膜片钳技术，研究了一系列脂肪醇对人胚肾（HEK）293细胞和幼年大鼠脑片丘脑皮质（TC）中继神经元表达的重组人Ca（V）3.1（α 1G）T通道亚型的抑制机制。辛醇、1-庚醇（heptanol）和1-己醇（hexanol）以浓度依赖性方式抑制重组Ca（V）3.1电流，IC 50值分别为362 μ M、1063 μ M和3167 μ M。辛醇类似地抑制天然丘脑Ca（V）3.1 T-电流，IC 50为287 μ M，并减少爆发性放电，而对这些神经元的被动膜特性无显著影响。辛醇对天然和重组细胞T电流的抑制作用伴随着宏观失活动力学的加速和稳态失活曲线的超极化偏移。此外，辛醇诱导TC神经元T电流稳态激活曲线的去极化偏移。令人惊讶的是，从快速失活在超极化膜电位的恢复加速了3倍，在天然但不是重组通道的辛醇。鉴于丘脑皮质通路在提供睡眠、觉醒和麻醉状态中的重要性，丘脑T电流的调节至少可能有助于脂肪醇的药理学作用。(C)2010爱思唯尔有限公司保留所有权利。
Many aliphatic alcohols modulate activity of various ion channels involved in sensory processing and also exhibit anesthetic capacity in vivo. Although the interaction of one such compound, 1-octanol (octanol) with different T-type calcium channels (T-channels) has been described, the mechanisms of current modulation and its functional significance are not well studied. Using patch-clamp technique, we investigated the mechanisms of inhibition of T-currents by a series of aliphatic alcohols in recombinant human Ca(V)3.1 (alpha 1G) T-channel isoform expressed in human embryonic kidney (HEK) 293 cells and thalamocortical (TC) relay neurons in brain slices of young rats. Octanol, 1-heptanol (heptanol) and 1-hexanol (hexanol) inhibited the recombinant Ca(V)3.1 currents in concentration-dependent manner yielding IC50 values of 362 mu M, 1063 mu M and 3167 mu M, respectively. Octanol similarly inhibited native thalamic Ca(V)3.1 T-currents with an IC50 of 287 mu M and diminished burst firing without significant effect on passive membrane properties of these neurons. Inhibitory effect of octanol on T-currents in both native and recombinant cells was accompanied with accelerated macroscopic inactivation kinetics and hyperpolarizing shift in the steady-state inactivation curve. Additionally, octanol induced a depolarizing shift in steady-state activation curves of T-current in TC neurons. Surprisingly, the recovery from fast inactivation at hyperpolarized membrane potentials was accelerated by octanol up 3-fold in native but not recombinant channels. Given the importance of thalamocortical pathways in providing sleep, arousal, and anesthetic states, modulation of thalamic T-currents may at least contribute to the pharmacological effects of aliphatic alcohols. (C) 2010 Elsevier Ltd. All rights reserved.