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

Rahul Srinivasan; Brandon J. Henderson; Henry A. Lester; Christopher I. Richards

doi:10.1016/j.phrs.2014.02.005

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

Rahul Srinivasan, Brandon J. Henderson, Henry A. Lester, Christopher I. Richards

Chemistry

Research output: Contribution to journal › Review article › peer-review

52 Scopus citations

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.

Original language	English
Pages (from-to)	20-29
Number of pages	10
Journal	Pharmacological Research
Volume	83
DOIs	https://doi.org/10.1016/j.phrs.2014.02.005
State	Published - May 2014

Bibliographical note

Funding Information:
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.

Funding

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.

Funders	Funder number
National Institutes of Health (NIH)
National Institute on Aging	R01AG033954
The Michael J Fox Foundation for Parkinson's Research
Tobacco-Related Disease Research Program	TRDRP 18FT-0066

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

ASJC Scopus subject areas

Pharmacology

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10.1016/j.phrs.2014.02.005

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title = "Pharmacological chaperoning of nAChRs: A therapeutic target for Parkinson's disease",

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",

author = "Rahul Srinivasan and Henderson, {Brandon J.} and Lester, {Henry A.} and Richards, {Christopher I.}",

note = "Funding Information: 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.",

year = "2014",

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doi = "10.1016/j.phrs.2014.02.005",

language = "English",

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T1 - Pharmacological chaperoning of nAChRs

T2 - A therapeutic target for Parkinson's disease

AU - Srinivasan, Rahul

AU - Henderson, Brandon J.

AU - Lester, Henry A.

AU - Richards, Christopher I.

N1 - Funding Information: 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.

PY - 2014/5

Y1 - 2014/5

N2 - 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.

AB - 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.

KW - COPI

KW - COPII

KW - Chaperoning

KW - Confocal

KW - Dopaminergic

KW - ER exit sites

KW - Endoplasmic reticulum stress

KW - FRET

KW - Golgi

KW - Ligand

KW - Neurodegeneration

KW - Neuroprotection

KW - Nicotine

KW - Parkinson's disease

KW - Pharmacological chaperone

KW - TIRF

KW - Tobacco

KW - Unfolded protein response

KW - nAChR

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M3 - Review article

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SN - 1043-6618

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JO - Pharmacological Research

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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