Srinivasan, Rahul and Richards, Christopher I. and Xiao, Cheng and Rhee, Doreen and Pantoja, Rigo and Dougherty, Dennis A. and Miwa, Julie M. and Lester, Henry A. (2012) Pharmacological Chaperoning of Nicotinic Acetylcholine Receptors Reduces the Endoplasmic Reticulum Stress Response. Molecular Pharmacology, 81 (6). pp. 759-769. ISSN 0026-895X http://resolver.caltech.edu/CaltechAUTHORS:20120530-081520292
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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 (α4_2β2_3 versus α4_3β2_2), 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.
|Additional Information:||© 2012 The American Society for Pharmacology and Experimental Therapeutics. Received January 13, 2012; accepted February 28, 2012. Published online before print February 29, 2012. 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.). We thank Johannes Schwarz for discussion, Elisha D. W. Mackey for assistance with cloning, and Sheri McKinney for assistance with primary neuronal cultures. Authorship Contributions: Participated in research design: Srinivasan, Richards, Pantoja, and Lester. Conducted experiments: Srinivasan, Richards, Xiao, Rhee, and Pantoja. Contributed new reagents or analytic tools: Srinivasan, Richards, and Miwa. Performed data analysis: Srinivasan, Richards, Xiao, and Lester. Wrote or contributed to the writing of the manuscript: Srinivasan, Richards, Dougherty, and Lester.|
|Official Citation:||Rahul Srinivasan, Christopher I. Richards, Cheng Xiao, Doreen Rhee, Rigo Pantoja, Dennis A. Dougherty, Julie M. Miwa, and Henry A. Lester Pharmacological Chaperoning of Nicotinic Acetylcholine Receptors Reduces the Endoplasmic Reticulum Stress Response Mol Pharmacol June 2012 81:759-769; published ahead of print February 29, 2012, doi:10.1124/mol.112.077792|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Ruth Sustaita|
|Deposited On:||30 May 2012 15:45|
|Last Modified:||30 May 2012 15:45|
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