title: Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery.
abstract: The acronym SePhaChARNS, for "selective pharmacological chaperoning of acetylcholine receptor number and stoichiometry," is introduced. We hypothesize that SePhaChARNS underlies classical observations that chronic exposure to nicotine causes "upregulation" of nicotinic receptors (nAChRs). If the hypothesis is proven, (1) SePhaChARNS is the molecular mechanism of the first step in neuroadaptation to chronic nicotine; and (2) nicotine addiction is partially a disease of excessive chaperoning. The chaperone is a pharmacological one, nicotine; and the chaperoned molecules are alpha4beta2* nAChRs. SePhaChARNS may also underlie two inadvertent therapeutic effects of tobacco use: (1) the inverse correlation between tobacco use and Parkinson's disease; and (2) the suppression of seizures by nicotine in autosomal dominant nocturnal frontal lobe epilepsy. SePhaChARNS arises from the thermodynamics of pharmacological chaperoning: ligand binding, especially at subunit interfaces, stabilizes AChRs during assembly and maturation, and this stabilization is most pronounced for the highest-affinity subunit compositions, stoichiometries, and functional states of receptors. Several chemical and pharmacokinetic characteristics render exogenous nicotine a more potent pharmacological chaperone than endogenous acetylcholine. SePhaChARNS is modified by desensitized states of nAChRs, by acid trapping of nicotine in organelles, and by other aspects of proteostasis. SePhaChARNS is selective at the cellular, and possibly subcellular, levels because of variations in the detailed nAChR subunit composition, as well as in expression of auxiliary proteins such as lynx. One important implication of the SePhaChARNS hypothesis is that therapeutically relevant nicotinic receptor drugs could be discovered by studying events in intracellular compartments rather than exclusively at the surface membrane.
authors.affiliation: Division of Biology 156-29, California Institute of Technology, Pasadena, CA 91125, USA. lester@caltech.edu
authors.forename: Henry A
authors.initials: HA
authors.lastname: Lester
authors.forename: Cheng
authors.initials: C
authors.lastname: Xiao
authors.forename: Rahul
authors.initials: R
authors.lastname: Srinivasan
authors.forename: Cagdas D
authors.initials: CD
authors.lastname: Son
authors.forename: Julie
authors.initials: J
authors.lastname: Miwa
authors.forename: Rigo
authors.initials: R
authors.lastname: Pantoja
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Banghart
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Dougherty
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Jen C
authors.initials: JC
authors.lastname: Wang
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D055808:Drug Discovery; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D017034:Epilepsy, Frontal Lobe / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D018377:Neurotransmitter Agents / Q000502:physiology; D009538:Nicotine / Q000493:pharmacokinetics / Q000494:pharmacology*; D010300:Parkinson Disease / Q000517:prevention & control; D011978:Receptors, Nicotinic / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D012907:Smoking / Q000378:metabolism; D014029:Tobacco Use Disorder / Q000235:genetics / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
chemical_list: D000109:Acetylcholine; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D009538:Nicotine; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; C523972:CHRNA5 protein, mouse