Regulation of Nicotinic Acetylcholine Receptor Numbers and Function by Chronic Nicotine Exposure
Regulation of Nicotinic Acetylcholine Receptor Numbers and Function by Chronic Nicotine Exposure
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DOI：
10.2174/1568007023339184
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发表时间：
2002-01-01
影响因子：
3
通讯作者：
Lukas, R. J.
中科院分区：
文献类型：
--
作者：
Gentry, C. L.;Lukas, R. J.
综述了尼古丁慢性暴露对烟碱型乙酰胆碱受体(NAChR)表达影响的研究进展。这些发现对nAChR在健康和疾病中的作用以及治疗神经和精神疾病的药物设计的影响进行了评估。大多数研究继续表明，长期接触尼古丁会导致所有研究的nAChR亚型中nAChR样结合或抗原位点的数量增加(“上调”)，但这些影响具有时间和剂量依赖性，并具有nAChR亚型亚型所特有的大小。这些效应似乎是基于转录后的，但涉及的机制仍然不清楚。除了值得注意的例外，大多数研究还表明，长期接触尼古丁会导致nAChR功能丧失的几个阶段(“脱敏”和更长时间的“持续失活”)，以回应急性尼古丁激动剂的挑战。尼古丁诱导的功能丧失的发病和恢复时间以及剂量依赖关系也是特定于nAChR亚型的。一些发现表明，上调和功能丧失并不是因果或机械相关的。这表明，在体内，上调并不像慢性尼古丁暴露的功能效应那样具有生理意义。相比之下，吸烟者的大脑尼古丁水平，以及细胞外空间的乙酰胆碱水平，显然处于会改变nAChR处于功能就绪或非激活状态之间的平衡的范围内。需要进一步的工作来阐明慢性尼古丁配体暴露的影响是如何跨nAChR亚型整合的，以及它们服务于产生尼古丁依赖和/或治疗益处的神经回路和化学信号通路。
Recent advances concerning effects of chronic nicotine exposure on nicotinic acetylcholine receptor (nAChR) expression are reviewed. Implications are assessed of these findings for roles of nAChR in health and disease and for design of drugs for treatment of neurological and psychiatric disorders. Most studies continue to show that chronic nicotine exposure induces increases in numbers of nAChR-like binding or antigenic sites ("upregulation') across all nAChR subtypes investigated, but with time- and dose-dependencies and magnitudes for these effects that are unique to subsets of nAChR subtypes. These effects appear to be post-transcriptionally based, but mechanisms involved remain obscure. With notable exceptions, most studies also show that chronic nicotine exposure induces several phases of nAChR functional loss ("desensitization" and longer-lasting "persistent inactivation") assessed in response to acute nicotinic agonist challenges. Times for onset and recovery and dose-dependencies for nicotine-induced functional loss also are nAChR subtype-specific. Some findings suggest that upregulation and functional loss are not causally- or mechanistically-related. It is suggested that upregulation is not as physiologically significant in vivo as functional effects of chronic nicotine exposure. By contrast, brain levels of nicotine in tobacco users, and perhaps levels of acetylcholine in the extracellular space, clearly are in the range that would alter the balance between nAChR in functionally ready or inactivated states. Further work is warranted to illuminate how effects of chronic nicotinic ligand exposure are integrated across nAChR subtypes and the neuronal circuits and chemical signaling pathways that they service to produce nicotine dependence and/or therapeutic benefit.