期刊
JOURNAL OF NEUROSCIENCE
卷 25, 期 23, 页码 5563-5572出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5240-04.2005
关键词
neuronal; nicotinic; acetylcholine receptor; upregulation; epibatidine; conformational change
资金
- NIDA NIH HHS [P01 DA019695, P01 DA019695-01A20001] Funding Source: Medline
Nicotine addiction is initiated by its binding to high-affinity nicotinic receptors in brain composed primarily of alpha 4 and beta 2 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 alpha 4 beta 2 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 alpha 4 beta 2 receptors in a high-affinity state that is more easily activated, thereby providing a memory for nicotine exposure.
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