Selective and regulated trapping of nicotinic receptor weak base ligands and relevance to smoking cessation

Anitha P. Govind, Yolanda F. Vallejo, Jacob R. Stolz, Jing Zhi Yan, Geoffrey T. Swanson, William N. Green*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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, blocking125I-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.

Original languageEnglish (US)
Article numbere25651
JournaleLife
Volume6
DOIs
StatePublished - Jul 18 2017

Funding

This work was supported by RO1 DA035430 and a Pilot Project from the University of Chicago Cancer Center. The authors would like to thank Drs. Okunola Jeyifous and Jary Delgado for assistance with rat brain dissections for cortical neuronal preparations, Drs. Steve Sine (human a4 and b2) and Chris Richards (a4 SEP) for their gifts of nAChR constructs. The authors declare that they have no competing interests.

ASJC Scopus subject areas

  • General Neuroscience
  • General Immunology and Microbiology
  • General Biochemistry, Genetics and Molecular Biology

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