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Pharmacol Res. 2014 May;83:20-9. doi: 10.1016/j.phrs.2014.02.005. Epub 2014 Mar 1.

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

Author information

1
Department of Physiology, University of California Los Angeles, Los Angeles, CA, United States. Electronic address: rahul.srinivasan@gmail.com.
2
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, United States.
3
Department of Chemistry, University of Kentucky, Lexington, KY, United States.

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.

KEYWORDS:

COPI; COPII; Chaperoning; Confocal; Dopaminergic; ER exit sites; Endoplasmic reticulum stress; FRET; Golgi; Ligand; Neurodegeneration; Neuroprotection; Nicotine; Parkinson's disease; Pharmacological chaperone; TIRF; Tobacco; Unfolded protein response; nAChR

PMID:
24593907
DOI:
10.1016/j.phrs.2014.02.005
[Indexed for MEDLINE]
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