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.

Cholinergic activity and levodopa‐induced dyskinesia: a multitracer molecular imaging study

“…This finding, together with the usual young disease onset of dyskinetic patients2, might support the notion of a neuroprotective effect of the cholinergic system on nigrostriatal dopamine‐containing neurons 49, 50, 51. In this study, we were not able to properly address a putative neuroprotective effect of the cholinergic system on nigrostriatal dopamine‐containing neurons and disease progression.…”

“…Further in vivo investigation into the role of acetylcholine, including different subtypes of receptors,50 is crucial for future development of new strategies for the pharmacological treatment of dyskinesias in patients with Parkinson's disease.…”

The Nicotine Metabolite, Cotinine, Alters the Assembly and Trafficking of a Subset of Nicotinic Acetylcholine Receptors

“…It is possible that cotinine-induced up-regulation results from a similar mechanism as nicotine, likely acting inside the cell by binding immature subunits to enhance the maturation and stabilization of nAChRs (18,52). This chaperoning process is not unique to nicotine, and can potentially occur with any ligand that readily permeates cell membranes and interacts with intracellular nAChRs.…”

“…Nicotine-induced changes in nAChRs have been proposed as a potential component in the mechanism for nicotine addiction (8,(13)(14)(15)(16)(17). The current pharmacological chaperoning hypothesis suggests that these changes only require concentrations of nicotine to be high enough to interact with the specific subtype in the endoplasmic reticulum, meaning surface activation is not required (8,18) Other nAChR ligands, including drugs that have been evaluated as smoking cessation agents, have also been shown to up-regulate nAChRs. These drugs include the partial agonists cytisine (19) and varenicline (20) as well as the antagonist mecamylamine (21).…”

The Sleep-Modulating Peptide Orexin-B Protects Midbrain Dopamine Neurons from Degeneration, Alone or in Cooperation with Nicotine

“…We were also interested in determining whether nicotine (NIC), a well known neuroprotective molecule for DA neurons (Quik et al, 2007;Srinivasan et al, 2014), had an impact on the effect of OX peptides. Our data demonstrate that OXB promotes DA cell survival in midbrain cultures through the activation of OX2R, and that NIC amplifies this effect through the activation of a7 nicotinic acetylcholine receptors (nAChRs).…”