title: Chronic nicotine exposure upregulates nicotinic receptors by a novel mechanism.
abstract: Nicotine addiction is initiated by its binding to high-affinity nicotinic receptors in brain composed primarily of alpha4 and beta2 subunits. For nicotinic receptors expressed in vivo or heterologously, nicotine exposure over hours to days increases or "upregulates" high-affinity nicotine binding to receptors through a posttranslational mechanism thought to increase receptor numbers. Using heterologous expression, we find nicotine exposure causes a fourfold to sixfold higher binding to alpha4beta2 receptors that does not correspond with any significant change in the number of surface receptors or a change in the assembly, trafficking, or cell-surface turnover of the receptors. However, upregulation does alter the functional state of the receptor, slowing desensitization and enhancing sensitivity to acetylcholine. Based on these findings, we propose an alternative mechanism to explain nicotine-induced upregulation in which nicotine exposure slowly stabilizes alpha4beta2 receptors in a high-affinity state that is more easily activated, thereby providing a memory for nicotine exposure.
authors.affiliation: Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Yolanda F
authors.initials: YF
authors.lastname: Vallejo
authors.forename: Bruno
authors.initials: B
authors.lastname: Buisson
authors.forename: Daniel
authors.initials: D
authors.lastname: Bertrand
authors.forename: William N
authors.initials: WN
authors.lastname: Green
mesh_terms: D019921:Biotinylation; D002460:Cell Line; D006801:Humans; D009538:Nicotine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000096:biosynthesis* / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine