title: Nicotine exploits a COPI-mediated process for chaperone-mediated up-regulation of its receptors.
abstract: Chronic exposure to nicotine up-regulates high sensitivity nicotinic acetylcholine receptors (nAChRs) in the brain. This up-regulation partially underlies addiction and may also contribute to protection against Parkinson's disease. nAChRs containing the α6 subunit (α6* nAChRs) are expressed in neurons in several brain regions, but comparatively little is known about the effect of chronic nicotine on these nAChRs. We report here that nicotine up-regulates α6* nAChRs in several mouse brain regions (substantia nigra pars compacta, ventral tegmental area, medial habenula, and superior colliculus) and in neuroblastoma 2a cells. We present evidence that a coat protein complex I (COPI)-mediated process mediates this up-regulation of α6* or α4* nAChRs but does not participate in basal trafficking. We show that α6β2β3 nAChR up-regulation is prevented by mutating a putative COPI-binding motif in the β3 subunit or by inhibiting COPI. Similarly, a COPI-dependent process is required for up-regulation of α4β2 nAChRs by chronic nicotine but not for basal trafficking. Mutation of the putative COPI-binding motif or inhibition of COPI also results in reduced normalized Förster resonance energy transfer between α6β2β3 nAChRs and εCOP subunits. The discovery that nicotine exploits a COPI-dependent process to chaperone high sensitivity nAChRs is novel and suggests that this may be a common mechanism in the up-regulation of nAChRs in response to chronic nicotine.
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Henderson
authors.forename: Rahul
authors.initials: R
authors.lastname: Srinivasan
authors.forename: Weston A
authors.initials: WA
authors.lastname: Nichols
authors.forename: Crystal N
authors.initials: CN
authors.lastname: Dilworth
authors.forename: Diana F
authors.initials: DF
authors.lastname: Gutierrez
authors.forename: Elisha D W
authors.initials: ED
authors.lastname: Mackey
authors.forename: Sheri
authors.initials: S
authors.lastname: McKinney
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Drenan
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Richards
authors.forename: Henry A
authors.initials: HA
authors.lastname: Lester
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D020755:Coat Protein Complex I / Q000378:metabolism*; D051379:Mice; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011485:Protein Binding; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D020755:Coat Protein Complex I; D018722:Nicotinic Agonists; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D009538:Nicotine