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The Journal of Neuroscience, June 8, 2005, 25(23):5563-5572; doi:10.1523/JNEUROSCI.5240-04.2005

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Cellular/Molecular
Chronic Nicotine Exposure Upregulates Nicotinic Receptors by a Novel Mechanism

Yolanda F. Vallejo,¹ Bruno Buisson,² Daniel Bertrand,² and William N. Green¹

¹Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois 60637, and ²Department of Neuroscience, Medical Faculty, University of Geneva, CH-1211 Geneva 4, Switzerland

Nicotine addiction is initiated by its binding to high-affinity nicotinic receptors in brain composed primarily of 4 and 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 42 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 42 receptors in a high-affinity state that is more easily activated, thereby providing a memory for nicotine exposure.

Key words: neuronal; nicotinic; acetylcholine receptor; upregulation; epibatidine; conformational change

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Received Dec 22, 2004; revised April 24, 2005; accepted April 27, 2005.

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