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Nicotine exploits a COPI-mediated process for chaperone-mediated up-regulation of its receptors

Henderson, Brandon J. and Srinivasan, Rahul and Nichols, Weston A. and Dilworth, Crystal N. and Gutierrez, Diana F. and Mackey, Elisha D. W. and McKinney, Sheri and Drenan, Ryan M. and Richards, Christopher I. and Lester, Henry A. (2013) Nicotine exploits a COPI-mediated process for chaperone-mediated up-regulation of its receptors. Journal of General Physiology, 143 (1). pp. 51-66. ISSN 0022-1295. PMCID PMC3874574. doi:10.1085/jgp.201311102.

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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.

Item Type:Article
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URLURL TypeDescription DOIArticle CentralArticle
Henderson, Brandon J.0000-0003-0381-028X
Drenan, Ryan M.0000-0002-8141-8577
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2014 Henderson et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at Submitted: 16 September 2013; accepted: 6 December 2013. Published December 30, 2013. We thank Jennifer Lippincott-Schwartz for kindly providing ɛCOPGFP subunits for our studies, Rell Parker for comments, and the Barbara Wold laboratory for providing cryosectioning tools. This work was supported by National Institutes of Health (grants AG033954, DA017279, DA019375, DA030396, NS034407, and DA033721) and by the California Tobacco-Related Disease Research Program (grant 17RT0127). Louis and Janet Fletcher provided partial funding for the TIRF microscope. The authors have no conflicting financial interests. Edward N. Pugh Jr. served as editor.
Funding AgencyGrant Number
California Tobacco-Related Disease Research Program17RT0127
Issue or Number:1
PubMed Central ID:PMC3874574
Record Number:CaltechAUTHORS:20140123-151832351
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:43497
Deposited By: Jason Perez
Deposited On:24 Jan 2014 15:28
Last Modified:10 Nov 2021 16:38

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