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Smoking-Relevant Nicotine Concentration Attenuates the Unfolded Protein Response in Dopaminergic Neurons

Srinivasan, Rahul and Henley, Beverley M. and Henderson, Brandon J. and Indersmitten, Tim and Cohen, Bruce N. and Kim, Charlene H. and McKinney, Sheri and Deshpande, Purnima and Xiao, Cheng and Lester, Henry A. (2016) Smoking-Relevant Nicotine Concentration Attenuates the Unfolded Protein Response in Dopaminergic Neurons. Journal of Neuroscience, 36 (1). pp. 65-79. ISSN 0270-6474. PMCID PMC4701966. doi:10.1523/JNEUROSCI.2126-15.2016.

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Retrospective epidemiological studies show an inverse correlation between susceptibility to Parkinson's disease and a person's history of tobacco use. Animal model studies suggest nicotine as a neuroprotective agent and nicotinic acetylcholine (ACh) receptors (nAChRs) as targets for neuroprotection, but the underlying neuroprotective mechanism(s) are unknown. We cultured mouse ventral midbrain neurons for 3 weeks. Ten to 20% of neurons were dopaminergic (DA), revealed by tyrosine hydroxylase (TH) immunoreactivity. We evoked mild endoplasmic reticulum (ER) stress with tunicamycin (Tu), producing modest increases in the level of nuclear ATF6, phosphorylated eukaryotic initiation factor 2α, nuclear XBP1, and the downstream proapoptotic effector nuclear C/EBP homologous protein. We incubated cultures for 2 weeks with 200 nm nicotine, the approximate steady-state concentration between cigarette smoking or vaping, or during nicotine patch use. Nicotine incubation suppressed Tu-induced ER stress and the unfolded protein response (UPR). Study of mice with fluorescent nAChR subunits showed that the cultured TH+ neurons displayed α4, α6, and β3 nAChR subunit expression and ACh-evoked currents. Gene expression profile in cultures from TH-eGFP mice showed that the TH+ neurons also express several other genes associated with DA release. Nicotine also upregulated ACh-induced currents in DA neurons by ∼2.5-fold. Thus, nicotine, at a concentration too low to activate an appreciable fraction of plasma membrane nAChRs, induces two sequelae of pharmacological chaperoning in the ER: UPR suppression and nAChR upregulation. Therefore, one mechanism of neuroprotection by nicotine is pharmacological chaperoning, leading to UPR suppression. Measuring this pathway may help in assessing neuroprotection.

Item Type:Article
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URLURL TypeDescription CentralArticle
Henderson, Brandon J.0000-0003-0381-028X
Xiao, Cheng0000-0001-9649-7450
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2016 the authors. Beginning six months after publication the Work will be made freely available to the public on SfN’s website to copy, distribute, or display under a Creative Commons Attribution 4.0 International (CC BY 4.0) license ( Received June 2, 2015; revised Nov. 9, 2015; accepted Nov. 13, 2015. This work was supported by grants from the U.S. National Institutes of Health (AG033954), the Michael J. Fox Foundation, and Louis and Janet Fletcher. We thank Dr. Marie-Françoise Chesselet for useful discussions and E. Mackey for help with antibody verification. The authors declare no competing financial interests. Author contributions: R.S., B.M.H., B.J.H., C.X., and H.A.L. designed research; R.S., B.M.H., B.J.H., T.I., B.N.C., C.H.K., S.M., P.D., and C.X. performed research; R.S., B.M.H., B.J.H. contributed unpublished reagents/analytic tools; R.S., B.M.H., B.J.H., T.I., B.N.C., C.X., and H.A.L. analyzed data; R.S., B.M.H., B.J.H., B.N.C., and H.A.L. wrote the paper. R.S. and B.M.H. contributed equally to this work.
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Michael J. Fox FoundationUNSPECIFIED
Louis and Janet FletcherUNSPECIFIED
Issue or Number:1
PubMed Central ID:PMC4701966
Record Number:CaltechAUTHORS:20160111-082423100
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:63525
Deposited By: Tony Diaz
Deposited On:13 Jan 2016 00:44
Last Modified:10 Nov 2021 23:17

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