Molecular mechanisms of the inhibitory effects of propofol and thiamylal on sarcolemmal adenosine triphosphate-sensitive potassium channels
Molecular mechanisms of the inhibitory effects of propofol and thiamylal on sarcolemmal adenosine triphosphate-sensitive potassium channels
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DOI：
10.1097/00000542-200402000-00024
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发表时间：
2004-02-01
期刊：
影响因子：
8.8
通讯作者：
Nakaya, Y
中科院分区：
文献类型：
--
作者：
Kawano, T;Oshita, S;Nakaya, Y
背景：丙泊酚和硫戊巴比妥均抑制三磷酸腺苷敏感性钾（K-ATP）通道。本研究观察了这些麻醉药对重组肌膜K-ATP通道活性的影响（Kir6.1或Kir6.2）基因与磺脲类药物受体方法：作者使用由内而外的膜片钳技术研究了异丙酚和硫代戊巴比妥对重组K-结果：异丙酚抑制了K-ATP通道亚基转染的COS-7细胞的SUR1/Kir6.2（EC_（50）= 77 μ M）、SUR2A/Kir6.2（EC_（50）= 72 μ M）和SUR2B/Kir6.2（EC_（50）= 71 μ M）通道的活性，但对SUR2B/Kir6.1通道无明显影响。丙泊酚抑制Kir6.2（Kir6.2DeltaC36）通道的截短亚型（EC 50 = 78 μ M），该通道可在缺少SUR分子的情况下形成功能性K-ATP通道。此外，作者确定了Kir6.2DeltaC36通道的两个不同突变R31E（31位精氨酸残基变为谷氨酸）和K185Q（185位赖氨酸残基变为谷氨酰胺），这两个突变显著降低了丙泊酚的抑制作用。与此相反，硫代戊醛抑制SUR1/Kir6.2（EC50 = 541 μ M）、SUR2A/Kir6.2（EC50 = 248 μ M）、SUR2B/Kir6.2（EC50 = 183 μ M）、SUR2B/Kir6.1（EC50 = 170 μ M）和Kir6.2DeltaC36通道（EC50 = 719 μ M）。没有突变体显着影响的敏感性甲硫氨酸。结论：这些结果表明，异丙酚和硫戊巴比妥对K-ATP通道活性的主要影响是通过Kir6.2亚基介导的。定点突变研究表明，丙泊酚和硫代戊醛可能通过不同的分子机制影响Kir6.2活性;在硫代戊醛中，SUR亚基似乎调节麻醉剂敏感性。
Background: Both propofol and thiamylal inhibit adenosine triphosphate-sensitive potassium (K-ATP) channels. in the current study, the authors investigated the effects of these anesthetics on the activity of recombinant sarcolemmal K-ATP channels encoded by inwardly rectifying potassium channel (Kir6.1 or Kir6.2) genes and sulfonylurea receptor (SUR1, SUR2A, or SUR2B) genes.Methods: The authors used inside-out patch clamp configurations to investigate the effects of propofol and thiamylal on the activity of recombinant K-ATP channels using COS-7 cells transfected with various types of K-ATP channel subunits.Results: Propofol inhibited the activities of the SUR1/Kir6.2 (EC50 = 77 muM), SUR2A/Kir6.2 (EC50 = 72 muM), and SUR2B/Kir6.2 (EC50 = 71 muM) channels but had no significant effects on the SUR2B/Kir6.1 channels. Propofol inhibited the truncated isoform of Kir6.2 (Kir6.2DeltaC36) channels (EC50 = 78 muM) that can form functional K-ATP channels in the absence of SUR molecules. Furthermore, the authors identified two distinct mutations R31E (arginine residue at position 31 to glutamic acid) and K185Q (lysine residue at position 185 to glutamine) of the Kir6.2DeltaC36 channel that significantly reduce the inhibition of propofol. In contrast, thiamylal inhibited the SUR1/Kir6.2 (EC50 = 541 muM), SUR2A/Kir6.2 (EC50 = 248 muM), SUR2B/Kir6.2 (EC50 = 183 muM), SUR2B/Kir6.1 (EC50 = 170 muM), and Kir6.2DeltaC36 channels (EC50 = 719 muM). None of the mutants significantly affects the sensitivity of thiamylal. Conclusions: These results suggest that the major effects of both propofol and thiamylal on K-ATP channel activity are mediated via the Kir6.2 subunit. Site-directed mutagenesis study suggests that propofol and thiamylal may influence Kir6.2 activity by different molecular mechanisms; in thiamylal, the SUR subunit seems to modulate anesthetic sensitivity.