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Nicotine is a Selective Pharmacological Chaperone of Acetylcholine Receptor Number and Stoichiometry. Implications for Drug Discovery

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  • Theme: NIDA Symposium: Drugs of Abuse: Cutting-edge Research Technologies
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Abstract

The acronym SePhaChARNS, for “selective pharmacological chaperoning of acetylcholine receptor number and stoichiometry,” is introduced. We hypothesize that SePhaChARNS underlies classical observations that chronic exposure to nicotine causes “upregulation” of nicotinic receptors (nAChRs). If the hypothesis is proven, (1) SePhaChARNS is the molecular mechanism of the first step in neuroadaptation to chronic nicotine; and (2) nicotine addiction is partially a disease of excessive chaperoning. The chaperone is a pharmacological one, nicotine; and the chaperoned molecules are α4β2* nAChRs. SePhaChARNS may also underlie two inadvertent therapeutic effects of tobacco use: (1) the inverse correlation between tobacco use and Parkinson’s disease; and (2) the suppression of seizures by nicotine in autosomal dominant nocturnal frontal lobe epilepsy. SePhaChARNS arises from the thermodynamics of pharmacological chaperoning: ligand binding, especially at subunit interfaces, stabilizes AChRs during assembly and maturation, and this stabilization is most pronounced for the highest-affinity subunit compositions, stoichiometries, and functional states of receptors. Several chemical and pharmacokinetic characteristics render exogenous nicotine a more potent pharmacological chaperone than endogenous acetylcholine. SePhaChARNS is modified by desensitized states of nAChRs, by acid trapping of nicotine in organelles, and by other aspects of proteostasis. SePhaChARNS is selective at the cellular, and possibly subcellular, levels because of variations in the detailed nAChR subunit composition, as well as in expression of auxiliary proteins such as lynx. One important implication of the SePhaChARNS hypothesis is that therapeutically relevant nicotinic receptor drugs could be discovered by studying events in intracellular compartments rather than exclusively at the surface membrane.

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Acknowledgments

Relevant work in the authors’ laboratories is supported by grants from NINDS (NS11756, NS34407), NIDA (DA17279, DA19375), NCI (CA089392), NIA (AG033954), NIAAA (AA08401), the Michael J. Fox Foundation, the California Tobacco-Related Disease Research Program, the Croll Autism Research Foundation (1004564-01-CEN5300443), and Targacept, Inc. Postdoctoral fellowships were awarded to C. S. from Philip Morris USA/International, to X. C. from the California Tobacco-Related Disease Research Program, and to R. P. from the Ford Foundation and APA-DPN.

Conflict of Interest Statement

Drs. Goate and Wang are listed as inventors on patent application US 2007/0258898 held by Perlegen Sciences Inc., covering the use of certain SNPs, including rs16969968 in diagnosing, prognosing, and treating addiction. Dr. Miwa acts as a consultant to Ophidion, Inc.

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  1. Division of Biology 156-29, California Institute of Technology, Pasadena, CA, 91125, USA

    Henry A. Lester, Cheng Xiao, Rahul Srinivasan, Cagdas D. Son, Julie Miwa & Rigo Pantoja

  2. Department of Neurobiology, Harvard Medical School, 220 Longwood Ave, Boston, MA, 02115, USA

    Matthew R. Banghart

  3. Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, 91125, USA

    Dennis A. Dougherty

  4. Washington University School of Medicine, St. Louis, MO, 63110, USA

    Alison M. Goate & Jen C. Wang

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  1. Henry A. Lester
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Lester, H.A., Xiao, C., Srinivasan, R. et al. Nicotine is a Selective Pharmacological Chaperone of Acetylcholine Receptor Number and Stoichiometry. Implications for Drug Discovery. AAPS J 11, 167–177 (2009). https://doi.org/10.1208/s12248-009-9090-7

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