Suppression of Ih contributes to propofol-induced inhibition of mouse cortical pyramidal neurons
Suppression of Ih contributes to propofol-induced inhibition of mouse cortical pyramidal neurons
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DOI：
10.1152/jn.00389.2005
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发表时间：
2005-12-01
影响因子：
2.5
通讯作者：
Bayliss, DA
中科院分区：
文献类型：
--
作者：
Chen, XD;Shu, SF;Bayliss, DA
对于各种中枢神经元，特别是在丘脑皮质回路中，超极化激活电流 1 小时对节律活动产生的贡献已得到很好的描述。在本研究中，我们研究了全身麻醉剂异丙酚对丘脑和皮质神经元天然 1 小时以及对相应克隆的 HCN 通道亚基的影响。小鼠脑切片的全细胞电压钳记录识别出神经元 1 小时电流在新皮质锥体神经元中具有快速激活动力学，而在丘脑皮质中继细胞中具有较慢的动力学。异丙酚在临床相关浓度（5μM）下抑制皮质神经元的快速激活1小时； 1小时的抑制涉及半激活电压的超极化转变（Delta V1/2大约-9 mV）和最大可用电流的减少（类似于36%抑制，在-120 mV测量）。对于丘脑皮质神经元中表达的较慢形式 1 小时，异丙酚对电流激活或幅度没有影响。在异源表达系统中，5 μM 丙泊酚引起同聚 HCN1 和连接的异聚 HCN1-HCN2 通道中 V1/2 的大幅变化和电流幅度的降低，这两种通道均以快速动力学激活，但不影响缓慢激活同聚 HCN2 通道的 V1/2 或电流幅度。通过阻断 GABA A 和甘氨酸受体通道，异丙酚引起膜超极化并抑制皮层神经元的动作电位放电；这些效应被 1 小时阻断剂 ZD-7288 阻断。总之，这些数据表明，异丙酚选择性抑制含有 HCN1 亚基的 HCN 通道，例如在皮质锥体神经元中介导 1 小时的通道，并且表明异丙酚的麻醉作用可能涉及抑制皮质神经元以及其他 HCN1 表达细胞。
The contributions of the hyperpolarization-activated current, 1 h, to generation of rhythmic activities are well described for various central neurons, particularly in thalamocortical circuits. In the present study, we investigated effects of a general anesthetic, propofol, on native 1 h in neurons of thalamus and cortex and on the corresponding cloned HCN channel subunits. Whole cell voltage-clamp recordings from mouse brain slices identified neuronal 1 h currents with fast activation kinetics in neocortical pyramidal neurons and with slower kinetics in thalamocortical relay cells. Propofol inhibited the fast-activating 1 h in cortical neurons at a clinically relevant concentration (5 mu M); inhibition of 1 h involved a hyperpolarizing shift in half-activation voltage (Delta V1/2 approximately -9 mV) and a decrease in maximal available current (similar to 36% inhibition, measured at -120 mV). With the slower form of 1 h expressed in thalamocortical neurons, propofol had no effect on current activation or amplitude. In heterologous expression systems, 5 mu M propofol caused a large shift in V1/2 and decrease in current amplitude in homomeric HCN1 and linked heteromeric HCN1-HCN2 channels, both of which activate with fast kinetics but did not affect V1/2 or current amplitude of slowly activating homomeric HCN2 channels. With GABA A and glycine receptor channels blocked, propofol caused membrane hyperpolarization and suppressed action potential discharge in cortical neurons; these effects were occluded by the 1 h blocker, ZD-7288. In summary, these data indicate that propofol selectively inhibits HCN channels containing HCN1 subunits, such as those that mediate 1 h in cortical pyramidal neurons and they suggest that anesthetic actions of propofol may involve inhibition of cortical neurons and perhaps other HCN1-expressing cells.