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Review
. 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

Rahul Srinivasan  1 , Brandon J Henderson  2 , Henry A Lester  2 , Christopher I Richards  3
Affiliations
Review

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

Rahul Srinivasan et al. Pharmacol Res. 2014 May.

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.

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Conflict of interest statement

Conflict of interest

The authors declare no competing financial interests.

Figures

Fig. 1.
Fig. 1.
Methods to study pharmacological chaperoning of nAChRs. A schematic of nAChR trafficking in cells is shown. Pentameric receptors (green) assemble in the endoplasmic reticulum (ER) and concentrate in ER exit sites (dark green vesicle). Receptors then traffic to the trans Golgi network (TGN) via the ER to Golgi intermediate compartment (ERGIC). During chaperoning, ligand bound nAChRs return from the Golgi to the ER via COPI vesicles (orange-red) and are then cycled back to the Golgi via COPII vesicles. Some ligand bound receptors enter secretory vesicles bound to the plasma membrane (PM) from the TGN (yellow vesicle), resulting in upregulation at the PM. Also depicted are the methods that have been developed to study nAChR trafficking at each stage of the cellular secretory pathway. FRET and confocal microscopy allow high-resolution measurement of nAChR assembly and trafficking between the ER and Golgi. As explained in the text, under certain conditions, TIRF microscopy can be used to study nAChRs in the peripheral ER, TGN and upregulation at the PM. Single molecule imaging using zeromode waveguides allows measurement of nAChR stoichiometry of isolated receptors at the PM. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
Fig. 2.
Fig. 2.
Pharmacological chaperoning of nAChR subtypes. The nAChR subtypes known to assemble in various brain regions is shown along with whether or not the particular subtype undergoes pharmacological chaperoning.
See this image and copyright information in PMC

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