Nicotine exploits a COPI-mediated process for chaperone-mediated up-regulation of its receptorsNicotine exploits COPI for up-regulation | Academic Article individual record
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.

author list (cited authors)
Henderson, B. J., Srinivasan, R., Nichols, W. A., Dilworth, C. N., Gutierrez, D. F., Mackey, E., ... Lester, H. A.
publication date
2014
publisher
published in
keywords
  • Amino Acid MotifsAnimalsBinding SitesBrainCell Line, TumorCoat Protein Complex IMiceNicotineNicotinic AgonistsProtein BindingProtein SubunitsProtein TransportReceptors, NicotinicUp-Regulation