期刊
AAPS JOURNAL
卷 11, 期 1, 页码 167-177出版社
SPRINGER
DOI: 10.1208/s12248-009-9090-7
关键词
ADNFLE; dopamine; GABA; proteostasis; upregulation
资金
- NINDS [NS11756, NS34407]
- NIA [AG033954]
- NIAAA [AA08401]
- Michael J. Fox Foundation
- California Tobacco-Related Disease Research Program
- Croll Autism Research Foundation [1004564-01CEN5300443]
- Targacept, Inc.
- Philip Morris USA/ International
- Ford Foundation
- APA-DPN
- NATIONAL CANCER INSTITUTE [P01CA089392] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS034407, R01NS011756, R37NS034407] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG033954] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [U10AA008401] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA017279, U19DA019375] Funding Source: NIH RePORTER
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 alpha 4 beta 2* 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.
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