Activation and inhibition of human muscular and neuronal nicotinic acetylcholine receptors by succinylcholine
Activation and inhibition of human muscular and neuronal nicotinic acetylcholine receptors by succinylcholine
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DOI：
10.1097/00000542-200604000-00017
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发表时间：
2006-04-01
期刊：
影响因子：
8.8
通讯作者：
Eriksson, LI
中科院分区：
文献类型：
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作者：
Jonsson, M;Dabrowski, M;Eriksson, LI
背景：琥珀酰胆碱是临床麻醉和急诊医学中应用最广泛的肌松药之一。虽然其临床优势和心血管副作用已为人所知，但其在人体烟碱型胆碱能受体系统中的作用机制尚不清楚。本研究旨在探讨琥珀胆碱对人肌肉和神经元型烟碱型乙酰胆碱受体(NAChR)亚型的影响。方法：非洲爪哇卵母细胞注射人信使RNA以获得肌肉和神经型nAChR亚型。用多通道双电极电压钳装置研究了天然配体乙酰胆碱和琥珀胆碱对受体的激活、脱敏和抑制作用。结果：琥珀胆碱呈浓度依赖性激活肌型nAChR，其EC50值为10.8 GRIT(95%可信区间，9.8~11.9微米)，初始激活后，琥珀胆碱使肌型nAChR失敏。琥珀胆碱对神经元型nAChR亚型α3β2、α3β4、α4β2或α7无激活作用，但对这些受体亚型的抑制作用较差，IC50值大于100mM。结论：琥珀胆碱可激活肌型nAChR，继而使其脱敏。观察到琥珀胆碱在临床相关浓度下不抑制突触前α3β2自身受体，这为琥珀胆碱诱导的神经肌肉阻滞中典型的强直性消退提供了可能的机制解释。最后，琥珀酰胆碱的心血管副作用(例如，快速性心律失常)不是通过自主神经节细胞α3β4亚型的直接激活介导的，因为琥珀酰胆碱不激活神经元的nAChRs。
Background: Succinylcholine is one of the most widely used muscle relaxants in clinical anesthesia and emergency medicine. Although the clinical advantages and cardiovascular side effects are well known, its mechanism of action within the human nicotinic cholinergic receptor system remains to be understood. The aim of this study was to investigate the effect of succinylcholine on human muscle and neuronal nicotinic acetylcholine receptor (nAChR) subtypes.Methods: Xenopus laevis oocytes were injected with human messenger RNA for muscle and neuronal nAChR subunits. Receptor activation, desensitization, and inhibition induced by the natural ligand acetylcholine or by succinylcholine was studied using a multichannel two-electrode voltage clamp setup. Responses were measured as peak current and net charge.Results: Succinylcholine concentration-dependently activated the muscle-type nAChR with an EC50 value of 10.8 grit (95% confidence interval, 9.8-11.9 mu M), and after the initial activation, succinylcholine desensitized the muscle-type nAChR. Succinylcholine did not activate the neuronal nAChR subtypes alpha 3 beta 2, alpha 3 beta 4, alpha 4 beta 2, or alpha 7 at concentrations up to 1 mM and was a poor inhibitor at these receptor subtypes, with IC50 values above 100 mu M.Conclusion: Succinylcholine activates the muscle-type nAChR followed by desensitization. The observation that succinylcholine does not inhibit the presynaptic alpha 3 beta 2 autoreceptor at clinically relevant concentrations provides a possible mechanistic explanation for the typical lack of tetanic fade in succinylcholine-induced neuromuscular blockade. Finally, cardiovascular side effects (e.g., tachyarrhythmias) of succinylcholine are not mediated via direct activation of the autonomic ganglionic alpha 3 beta 4 subtype because succinylcholine does not activate the neuronal nAChRs.