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

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

Research output: Contribution to journalReview articlepeer-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 languageEnglish
Pages (from-to)20-29
Number of pages10
JournalPharmacological Research
Volume83
DOIs
StatePublished - 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.

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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