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J. Biol. Chem., Vol. 283, Issue 10, 6022-6032, March 7, 2008

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Up-regulation of Nicotinic Receptors by Nicotine Varies with Receptor Subtype^*

Heather Walsh, Anitha P. Govind, Ryan Mastro, J. C. Hoda, Daniel Bertrand, Yolanda Vallejo, and William N. Green¹

From the Department of Neurobiology, University of Chicago, Chicago, Illinois 60637 and Department of Neuroscience, Medical Faculty, University of Geneva, CH-1211 Geneva 4, Switzerland

Recent evidence suggests that in addition to 4β2 and 3-containing nicotinic receptors, 6-containing receptors are present in midbrain dopaminergic neurons and involved in the nicotine reward pathway. Using heterologous expression, we found that 6β2, like 3β2 and 4β2 receptors, formed high affinity epibatidine binding complexes that are pentameric, trafficked to the cell surface, and produced acetylcholine-evoked currents. Chronic nicotine exposure up-regulated 6β2 receptors with differences in up-regulation time course and concentration dependence compared with 4β2 receptors, the predominant high affinity nicotine binding site in brain. The 6β2 receptor up-regulation required higher nicotine concentrations than for 4β2 but lower than for 3β2 receptors. The 6β2 up-regulation occurred 10-fold faster than for 4β2 and slightly faster than for 3β2. Our data suggest that nicotinic receptor up-regulation is subtype-specific such that 6-containing receptors up-regulate in response to transient, high nicotine exposures, whereas sustained, low nicotine exposures up-regulate 4β2 receptors.

Received for publication, April 24, 2007 , and in revised form, January 2, 2008.

^* This research was supported by grants from the NIDA, National Institute of Health and Alzheimer's Association (W. N. G.), the Swiss National Science Foundation (to D. B.), and a fellowship from Philip Morris Inc. (to Y. F. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 947 E. 58th St., Chicago, IL 60637. Tel.: 773-702-1763; Fax: 773-702-3774; E-mail: wgreen{at}midway.uchicago.edu.

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