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Inside-out neuropharmacology of nicotinic drugs

Henderson, Brandon J. and Lester, Henry A. (2015) Inside-out neuropharmacology of nicotinic drugs. Neuropharmacology, 96 . pp. 178-193. ISSN 0028-3908. PMCID PMC4486611. doi:10.1016/j.neuropharm.2015.01.022.

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Upregulation of neuronal nicotinic acetylcholine receptors (AChRs) is a venerable result of chronic exposure to nicotine; but it is one of several consequences of pharmacological chaperoning by nicotine and by some other nicotinic ligands, especially agonists. Nicotinic ligands permeate through cell membranes, bind to immature AChR oligomers, elicit incompletely understood conformational reorganizations, increase the interaction between adjacent AChR subunits, and enhance the maturation process toward stable AChR pentamers. These changes and stabilizations in turn lead to increases in both anterograde and retrograde traffic within the early secretory pathway. In addition to the eventual upregulation of AChRs at the plasma membrane, other effects of pharmacological chaperoning include modifications to endoplasmic reticulum stress and to the unfolded protein response. Because these processes depend on pharmacological chaperoning within intracellular organelles, we group them as “inside-out pharmacology”. This term contrasts with the better-known, acute, “outside-in” effects of activating and desensitizing plasma membrane AChRs. We review current knowledge concerning the mechanisms and consequences of inside-out pharmacology.

Item Type:Article
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URLURL TypeDescription CentralArticle
Henderson, Brandon J.0000-0003-0381-028X
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2015 Published by Elsevier Ltd. Available online 4 February 2015. This work was supported by National Institutes of Health Grants AG033954, DA017279, DA019375, DA030396, NS034407, and DA033721, by the California Tobacco-Related Disease Research Program Grant 17RT0127, and by Louis and Janet Fletcher. We thank Sherry Leonard for contributing comments.
Funding AgencyGrant Number
California Tobacco-Related Disease Research Program17RT0127
Subject Keywords:Chaperoning; Nicotine; Nicotine addiction; Nicotinic receptors; Unfolded protein response; Upregulation
PubMed Central ID:PMC4486611
Record Number:CaltechAUTHORS:20150211-075813471
Persistent URL:
Official Citation:Brandon J. Henderson, Henry A. Lester, Inside-out neuropharmacology of nicotinic drugs, Neuropharmacology, Volume 96, Part B, September 2015, Pages 178-193, ISSN 0028-3908, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:54687
Deposited By: Tony Diaz
Deposited On:12 Feb 2015 00:52
Last Modified:10 Nov 2021 20:36

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