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Pharmacological chaperoning of nAChRs: A therapeutic target for Parkinson's disease

Srinivasan, Rahul and Henderson, Brandon J. and Lester, Henry A. and Richards, Christopher I. (2014) Pharmacological chaperoning of nAChRs: A therapeutic target for Parkinson's disease. Pharmacological Research, 83 . pp. 20-29. ISSN 1043-6618. PMCID PMC6075820. doi:10.1016/j.phrs.2014.02.005. https://resolver.caltech.edu/CaltechAUTHORS:20140724-150050094

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Abstract

Chronic exposure to nicotine results in an upregulation of neuronal nicotinic acetylcholine receptors (nAChRs) at the cellular plasma membrane. nAChR upregulation occurs via nicotine-mediated pharmacological receptor chaperoning and is thought to contribute to the addictive properties of tobacco as well as relapse following smoking cessation. At the subcellular level, pharmacological chaperoning by nicotine and nicotinic ligands causes profound changes in the structure and function of the endoplasmic reticulum (ER), ER exit sites, the Golgi apparatus and secretory vesicles of cells. Chaperoning-induced changes in cell physiology exert an overall inhibitory effect on the ER stress/unfolded protein response. Cell autonomous factors such as the repertoire of nAChR subtypes expressed by neurons and the pharmacological properties of nicotinic ligands (full or partial agonist versus competitive antagonist) govern the efficiency of receptor chaperoning and upregulation. Together, these findings are beginning to pave the way for developing pharmacological chaperones to treat Parkinson's disease and nicotine addiction.


Item Type:Article
Related URLs:
URLURL TypeDescription
httpS://doi.org/10.1016/j.phrs.2014.02.005DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075820PubMed CentralArticle
ORCID:
AuthorORCID
Henderson, Brandon J.0000-0003-0381-028X
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2014 Elsevier Ltd. Received 31 December 2013; Received in revised form 18 February 2014; Accepted 18 February 2014. Supported by grants from the Tobacco-Related Disease Research Program (TRDRP 18FT-0066), the Michael J Fox Foundation (MJFF), U.S. National Institutes of Health, Louis and Janet Fletcher. The authors declare no competing financial interests.
Funders:
Funding AgencyGrant Number
California Tobacco-Related Disease Research Program18FT-0066
Michael J. Fox FoundationUNSPECIFIED
NIHUNSPECIFIED
Louis and Janet FletcherUNSPECIFIED
Subject Keywords:Pharmacological chaperone; Chaperoning; Nicotine; nAChR; Tobacco; Neuroprotection; Parkinson's disease; Neurodegeneration; Unfolded protein response; Dopaminergic; Endoplasmic reticulum stress; FRET; TIRF; Confocal; ER exit sites; Golgi; Ligand; COPII; COPI
PubMed Central ID:PMC6075820
DOI:10.1016/j.phrs.2014.02.005
Record Number:CaltechAUTHORS:20140724-150050094
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20140724-150050094
Official Citation:Srinivasan, R., Henderson, B. J., Lester, H. A., & Richards, C. I. (2014). Pharmacological chaperoning of nAChRs: A therapeutic target for Parkinson's disease. Pharmacological Research, 83(0), 20-29. doi: http://dx.doi.org/10.1016/j.phrs.2014.02.005
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:47478
Collection:CaltechAUTHORS
Deposited By: Joanne McCole
Deposited On:24 Jul 2014 22:52
Last Modified:10 Nov 2021 17:40

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