Vallejo Yolanda F, Buisson Bruno, Bertrand Daniel, Green William N
Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois 60637, USA.
J Neurosci. 2005 Jun 8;25(23):5563-72. doi: 10.1523/JNEUROSCI.5240-04.2005.
Nicotine addiction is initiated by its binding to high-affinity nicotinic receptors in brain composed primarily of alpha4 and beta2 subunits. For nicotinic receptors expressed in vivo or heterologously, nicotine exposure over hours to days increases or "upregulates" high-affinity nicotine binding to receptors through a posttranslational mechanism thought to increase receptor numbers. Using heterologous expression, we find nicotine exposure causes a fourfold to sixfold higher binding to alpha4beta2 receptors that does not correspond with any significant change in the number of surface receptors or a change in the assembly, trafficking, or cell-surface turnover of the receptors. However, upregulation does alter the functional state of the receptor, slowing desensitization and enhancing sensitivity to acetylcholine. Based on these findings, we propose an alternative mechanism to explain nicotine-induced upregulation in which nicotine exposure slowly stabilizes alpha4beta2 receptors in a high-affinity state that is more easily activated, thereby providing a memory for nicotine exposure.
尼古丁成瘾是由其与大脑中主要由α4和β2亚基组成的高亲和力烟碱型受体结合引发的。对于体内表达或异源表达的烟碱型受体，数小时至数天的尼古丁暴露会通过一种翻译后机制增加或“上调”高亲和力尼古丁与受体的结合，这种机制被认为会增加受体数量。利用异源表达，我们发现尼古丁暴露导致与α4β2受体的结合增加了四倍至六倍，这与表面受体数量的任何显著变化、受体的组装、运输或细胞表面周转的变化均不对应。然而，上调确实会改变受体的功能状态，减缓脱敏作用并增强对乙酰胆碱的敏感性。基于这些发现，我们提出了一种替代机制来解释尼古丁诱导的上调，即尼古丁暴露会使α4β2受体缓慢稳定在更容易被激活的高亲和力状态，从而为尼古丁暴露提供一种记忆。
