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

Lester, Henry A. and Xiao, Cheng and Srinivasan, Rahul and Son, Cagdas D. and Miwa, Julie and Pantoja, Rigo and Banghart, Matthew R. and Dougherty, Dennis A. and Goate, Alison M. and Wang, Jen C. (2009) Nicotine is a Selective Pharmacological Chaperone of Acetylcholine Receptor Number and Stoichiometry. Implications for Drug Discovery. AAPS Journal, 11 (1). pp. 167-177. ISSN 1550-7416. PMCID PMC2664890. doi:10.1208/s12248-009-9090-7. https://resolver.caltech.edu/CaltechAUTHORS:20090707-084125313

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1208/s12248-009-9090-7DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664890/PubMed CentralArticle
http://rdcu.be/yb0zPublisherFree ReadCube access
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Xiao, Cheng0000-0001-9649-7450
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2009 American Association of Pharmaceutical Scientists. Received 31 December 2008; accepted 7 February 2009; published online 12 March 2009. 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.
Funders:
Funding AgencyGrant Number
NIHNS11756
NIHNS34407
NIHAG033954
NIHAA08401
Michael J. Fox FoundationUNSPECIFIED
California Tobacco-Related Disease Research ProgramUNSPECIFIED
Croll Autism Research Foundation1004564-01CEN5300443
Targacept, Inc.UNSPECIFIED
Philip Morris USA/ InternationalUNSPECIFIED
Ford FoundationUNSPECIFIED
American Psychological AssociationUNSPECIFIED
NIHCA089392
National Institute of Neurological Disorders and Stroke (NINDS)UNSPECIFIED
National Cancer InstituteUNSPECIFIED
National Institute on AgingUNSPECIFIED
National Institute on Alcohol Abuse and AlcoholismUNSPECIFIED
Subject Keywords:ADNFLE; dopamine; GABA; proteostasis; upregulation
Issue or Number:1
PubMed Central ID:PMC2664890
DOI:10.1208/s12248-009-9090-7
Record Number:CaltechAUTHORS:20090707-084125313
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20090707-084125313
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14504
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:12 Aug 2009 16:04
Last Modified:08 Nov 2021 23:12

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