Selective and regulated trapping of nicotinic receptor weak base ligands and relevance to smoking cessation
- University of Chicago, United States
- National Institute of Dental and Craniofacial Research, National Institutes of Health, United States
- Northwestern University, Feinberg School of Medicine, United States
Abstract
To better understand smoking cessation, we examined the actions of varenicline (Chantix) during long-term nicotine exposure. Varenicline reduced nicotine upregulation of α4β2-type nicotinic receptors (α4β2Rs) in live cells and neurons, but not for membrane preparations. Effects on upregulation depended on intracellular pH homeostasis and were not observed if acidic pH in intracellular compartments was neutralized. Varenicline was trapped as a weak base in acidic compartments and slowly released, blocking 125I-epibatidine binding and desensitizing α4β2Rs. Epibatidine itself was trapped; 125I-epibatidine slow release from acidic vesicles was directly measured and required the presence of α4β2Rs. Nicotine exposure increased epibatidine trapping by increasing the numbers of acidic vesicles containing α4β2Rs. We conclude that varenicline as a smoking cessation agent differs from nicotine through trapping in α4β2R-containing acidic vesicles that is selective and nicotine-regulated. Our results provide a new paradigm for how smoking cessation occurs and suggest how more effective smoking cessation reagents can be designed.
Article and author information
Author details
Funding
National Institutes of Health (RO1DA 035430)
- Anitha P Govind
- Yolanda F Vallejo
- Jacob R Stolz
- Jing-Zhi Yan
- Geoffrey T Swanson
- William N Green
University of Chicago (Cance center-Pilot grant)
- Anitha P Govind
- William N Green
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Govind et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Selective and regulated trapping of nicotinic receptor weak base ligands and relevance to smoking cessation
eLife 6:e25651.
https://doi.org/10.7554/eLife.25651
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