Volatile anaesthetics have differential effects on recombinant m1 and m3 muscarinic acetylcholine receptor function
Volatile anaesthetics have differential effects on recombinant m1 and m3 muscarinic acetylcholine receptor function
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DOI：
10.1093/bja/81.4.569
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发表时间：
1998-10-01
影响因子：
9.8
通讯作者：
Durieux, ME
中科院分区：
文献类型：
--
作者：
Nietgen, GW;Hönemann, CW;Durieux, ME
毒蕈碱乙酰胆碱信号传导在意识、认知功能、疼痛感知和循环稳态的调节中起重要作用。氟烷已显示出抑制mi毒蕈碱信号传导。然而，没有地氟烷、七氟烷或异氟烷的比较数据，也没有研究对m3亚型（在大脑中也很突出）的麻醉作用。因此，我们研究了这些化合物对分离的mi和m3毒蕈碱受体功能的影响。对表达重组m1或m3毒蕈碱或（作为比较）AT（1A）血管紧张素II受体的去卵泡非洲爪蟾卵母细胞进行电压钳位，并在存在临床相关浓度的氟烷、七氟烷、地氟烷或异氟烷的情况下测量由乙酰-β-甲基胆碱（Mch）或血管紧张素II诱导的Ca 2+激活的Cl-电流（I-Cl（Ca））。为了确定挥发性麻醉剂的作用部位，我们比较了麻醉剂对mi、m3和AT（1A）受体功能的影响，并研究了挥发性麻醉剂对细胞内注射第二信使IP 3诱导的信号传导的影响。地氟烷对mi信号传导具有双相作用，浓度为0.46 mmol/L（-1）时增强，但浓度为0.92 mmol/L（-1）时抑制。在m3信号传导中观察到类似的趋势，尽管不显著。异氟醚对mi信号传导没有影响，但能显著抑制m3信号传导。七氟烷以剂量依赖性方式抑制mi和m3信号传导的功能。氟烷，类似于其对mi信号传导的已知作用，剂量依赖性地抑制m3功能。I-Cl（Ca），诱导细胞内注射的IP 3不受所有四种麻醉剂。同样地，测试的麻醉剂都不影响AT（1A）信号。对AT（1A）信号传导和细胞内途径无干扰表明麻醉剂对毒蕈碱信号传导的影响很可能是由于与m1或m3受体分子的相互作用。具有不同亲和力的多个相互作用位点可以解释对地氟烷的双相反应。麻醉剂对密切相关的受体亚型的特异性作用表明挥发性麻醉剂对受体蛋白的作用部位明确。
Muscarinic acetylcholine signalling plays major roles in regulation of consciousness, cognitive Functioning, pain perception and circulatory homeostasis. Halothane has been shown to inhibit mi muscarinic signalling. However, no comparative data are available for desflurane, sevoflurane or isoflurane, nor have the anaesthetic effects on the m3 subtype (which is also prominent in the brain) been studied. Therefore, we have investigated the effects of these compounds on isolated mi and m3 muscarinic receptor function. Defolliculated Xenopus oocytes expressing recombinant mi or m3 muscarinic or (for comparison) AT(1A) angiotensin II receptors were voltage clamped, and Ca2+-activated Cl- currents (I-Cl(Ca)) induced by acetyl-beta-methylcholine (Mch) or angiotensin II were measured in the presence of clinically relevant concentrations of halothane, sevoflurane, desflurane or isoflurane. To determine the site of action of the volatile anaesthetics we compared anaesthetic effects on mi, m3 and AT(1A) receptor function and studied the effects of volatile anaesthetics on signalling induced by intracellular injection of the second messenger IP3. Desflurane had a biphasic effect on mi signalling, enhancing at a concentration of 0.46 mmol litre(-1) but depressing at 0.92 mmol litre(-1). A similar, although not significant, trend was observed with m3 signalling. Isoflurane had no effect on mi signalling, but profoundly inhibited m3 signalling. Sevoflurane depressed the function of mi and m3 signalling in a dose-dependent manner. Halothane, similar to its known effect on mi signalling, dose-dependently depressed m3 function. I-Cl(Ca), induced by intracellular injections of IP3 were unaffected by all four anaesthetics. Similarly, none of the anaesthetics tested affected AT(1A) signalling. Absence of interference with AT(1A) signalling and intracellular pathways suggest that the effects of anaesthetics On muscarinic signalling most likely result from interactions with the mi or m3 receptor molecule. Multiple interaction sites with different affinities may explain the biphasic response to desflurane. Anaesthetic-specific effects on closely related receptor subtypes suggest defined sites of action for volatile anaesthetics on the receptor protein.