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Molecular Pharmacology

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Research ArticleArticle

Pharmacological Chaperoning of Nicotinic Acetylcholine Receptors Reduces the Endoplasmic Reticulum Stress Response

Rahul Srinivasan, Christopher I. Richards, Cheng Xiao, Doreen Rhee, Rigo Pantoja, Dennis A. Dougherty, Julie M. Miwa and Henry A. Lester
Molecular Pharmacology June 2012, 81 (6) 759-769; DOI: https://doi.org/10.1124/mol.112.077792
Rahul Srinivasan
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Christopher I. Richards
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Cheng Xiao
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Doreen Rhee
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Rigo Pantoja
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Dennis A. Dougherty
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Julie M. Miwa
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Henry A. Lester
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Abstract

We report the first observation that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) can decrease when a central nervous system drug acts as an intracellular pharmacological chaperone for its classic receptor. Transient expression of α4β2 nicotinic receptors (nAChRs) in Neuro-2a cells induced the nuclear translocation of activating transcription factor 6 (ATF6), which is part of the UPR. Cells were exposed for 48 h to the full agonist nicotine, the partial agonist cytisine, or the competitive antagonist dihydro-β-erythroidine; we also tested mutant nAChRs that readily exit the ER. Each of these four manipulations increased Sec24D-enhanced green fluorescent protein fluorescence of condensed ER exit sites and attenuated translocation of ATF6-enhanced green fluorescent protein to the nucleus. However, we found no correlation among the manipulations regarding other tested parameters [i.e., changes in nAChR stoichiometry (α42β23 versus α43β22), changes in ER and trans-Golgi structures, or the degree of nAChR up-regulation at the plasma membrane]. The four manipulations activated 0 to 0.4% of nAChRs, which shows that activation of the nAChR channel did not underlie the reduced ER stress. Nicotine also attenuated endogenously expressed ATF6 translocation and phosphorylation of eukaryotic initiation factor 2α in mouse cortical neurons transfected with α4β2 nAChRs. We conclude that, when nicotine accelerates ER export of α4β2 nAChRs, this suppresses ER stress and the UPR. Suppression of a sustained UPR may explain the apparent neuroprotective effect that causes the inverse correlation between a person's history of tobacco use and susceptibility to developing Parkinson's disease. This suggests a novel mechanism for neuroprotection by nicotine.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS11756]; the National Institutes of Health National Institute on Aging [Grant AG033954]; National Institutes of Health National Institute on Drug Abuse Kirschstein National Research Service Award [Grant DA030877] (to C.I.R.); Targacept; Louis and Janet Fletcher; the Michael J. Fox Foundation; a California Tobacco-Related Disease Research Program postdoctoral fellowship [Grant 18FT-0066] (to R.S.); a Beckman Institute fellowship (to C.I.R.); and a California Tobacco-Related Disease Research Program New Investigator Award [Grant 19KT-0032] (to J.M.M.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.077792.

  • ABBREVIATIONS:

    ATF6
    activating transcription factor 6
    BT
    bleedthrough
    CHOP
    C/EBP homologous protein
    DHβE
    dihydro-β-erythroidine
    eCFP
    enhanced cyan fluorescent protein
    eGFP
    enhanced green fluorescent protein
    eIF2α
    eukaryotic initiation factor 2α
    peIF2α
    phosphorylated eukaryotic initiation factor 2α
    ER
    endoplasmic reticulum
    ERES
    endoplasmic reticulum exit site(s)
    Whigh
    fractional area of high-normalized Förster resonance energy transfer component
    FRET
    Förster resonance energy transfer
    nAChR
    nicotinic acetylcholine receptor
    NFRET
    normalized Förster resonance energy transfer
    PERK
    protein kinase RNA-like endoplasmic reticulum kinase
    PM
    plasma membrane
    ROI
    region of interest
    SePhaChARNS
    selective pharmacological chaperoning of acetylcholine receptor number and stoichiometry
    TG
    trans-Golgi
    TGN
    trans-Golgi network
    TIRFM
    total internal reflection fluorescence microscopy
    UPR
    unfolded protein response
    wt
    wild-type
    GalT
    galactosyltransferase
    FBS
    fetal bovine serum
    DMEM
    Dulbecco's modified Eagle's medium
    TBS
    Tris-buffered saline.

  • Received January 13, 2012.
  • Accepted February 28, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (6)
Molecular Pharmacology
Vol. 81, Issue 6
1 Jun 2012
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Research ArticleArticle

UPR Suppressed by Ligand-nAChR Interactions in ER

Rahul Srinivasan, Christopher I. Richards, Cheng Xiao, Doreen Rhee, Rigo Pantoja, Dennis A. Dougherty, Julie M. Miwa and Henry A. Lester
Molecular Pharmacology June 1, 2012, 81 (6) 759-769; DOI: https://doi.org/10.1124/mol.112.077792

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Research ArticleArticle

UPR Suppressed by Ligand-nAChR Interactions in ER

Rahul Srinivasan, Christopher I. Richards, Cheng Xiao, Doreen Rhee, Rigo Pantoja, Dennis A. Dougherty, Julie M. Miwa and Henry A. Lester
Molecular Pharmacology June 1, 2012, 81 (6) 759-769; DOI: https://doi.org/10.1124/mol.112.077792
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