Differential desensitization properties of rat neuronal nicotinic acetylcholine receptor subunit combinations expressed in Xenopus laevis oocytes.
Differential desensitization properties of rat neuronal nicotinic acetylcholine receptor subunit combinations expressed in Xenopus laevis oocytes.
复制标题
非洲爪蟾卵母细胞中表达的大鼠神经元烟碱乙酰胆碱受体亚基组合的差异脱敏特性。
DOI：
10.1007/bf02071877
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发表时间：
1995
影响因子：
4
通讯作者：
Ochoa,EL
中科院分区：
文献类型：
--
作者：
Vibat,CR;Lasalde,JA;McNamee,MG;Ochoa,EL
1.长期给予尼古丁上调哺乳动物神经元烟碱乙酰胆碱受体（nAChR）。解释上调的一个关键假设假设是尼古丁诱导受体功能脱敏。这与行为上表达的对药物的耐受性相关。（a）获得关于尼古丁诱导的神经元nAChR功能脱敏的信息，与肌肉和电鱼受体对应物相比，这是一种较少理解的现象;（B）检验不同受体亚基组合表现出不同脱敏模式的假设。3.将编码大鼠受体亚基α2，α3，或α4与β2亚基成对组合。采用双电极电压钳技术分析不同浓度乙酰胆碱（ACh）或尼古丁对神经元的刺激反应.浓度效应曲线表明，尼古丁是更有效的比乙酰胆碱的所有受体亚基组合测试。只有α4β2组合在浓度高于20µM尼古丁时表现出最大效应的抑制作用。5.单次尼古丁脉冲后，α4β2的受体脱敏（计算为单次指数衰减）显著慢于α3β2或α2β 2。6。在四分钟的循环中施用、洗涤和重新施用达到接近最大效果的尼古丁浓度。响应被计算为由初始应用诱发的电流的百分比。在该方案16分钟后，与α2β2和α3β2亚基组合相比，α4β2组合显示出原始应答的更大降低。综合第5点和第6点，这些实验表明α4β2受体亚型脱敏的速度较慢，并且在脱敏状态下保持的时间更长。由于α4β2是大脑内的主要受体亚基组合，并被尼古丁上调，因此我们的数据对于理解对这种药物耐受性的分子基础可能很重要。
1. Chronic administration of nicotine up-regulates mammalian neuronal nicotinic acetylcholine receptors (nAChRs). A key hypothesis that explains up-regulation assumes that nicotine induces desensitization of receptor function. This is correlated with behaviorally expressed tolerance to the drug.2. The present experiments were conducted to: (a) obtain information on the nicotine-induced desensitization of neuronal nAChR function, a less understood phenomenon as compared to that of the muscle and electric fish receptor counterparts; (b) test the hypothesis that different receptor subunit combinations exhibit distinct desensitization patterns.3.Xenopus laevisoocytes were injected with mRNAs encoding rat receptor subunitsα2,α3, orα4 in pairwise combination with theβ2 subunit. The responses to various concentrations of acetylcholine (ACh) or nicotine were analyzed by the two electrode voltage clamp technique.4. Concentration-effect curves showed that nicotine was more potent than ACh for all the receptor subunit combinations tested. Only theα4β2 combination exhibited a depression of the maximum effect at concentrations higher than 20µM nicotine.5. After a single nicotine pulse, receptor desensitization (calculated as a single exponential decay) was significantly slower forα4β2 than for eitherα3β2 orα2β2.6. Concentrations of nicotine that attained a near maximum effect were applied, washed, and re-applied in four minute cycles. The responses were calculated as percentages of the current evoked by the initial application. Following 16 minutes of this protocol, theα4β2 combination showed a greater reduction of the original response as compared to theα2β2 andα3β2 subunit combinations. Taking points 5 and 6 together, these experiments suggest that theα4β2 receptor subtype desensitizes at a slower rate and remains longer in the desensitized state.7. Becauseα4β2 is the main receptor subunit combination within the brain and is up-regulated by nicotine, our data may be important for understanding the molecular basis of tolerance to this drug.