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Deletion of lynx1 reduces the function of α6* nicotinic receptors

Parker, Rell L. and O’Neill, Heidi C. and Henley, Beverley M. and Wageman, Charles R. and Drenan, Ryan M. and Marks, Michael J. and Miwa, Julie M. and Grady, Sharon R. and Lester, Henry A. (2017) Deletion of lynx1 reduces the function of α6* nicotinic receptors. PLoS ONE, 12 (12). Art. No. e0188715. ISSN 1932-6203. https://resolver.caltech.edu/CaltechAUTHORS:20171211-155148787

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Abstract

The α6 nicotinic acetylcholine receptor (nAChR) subunit is an attractive drug target for treating nicotine addiction because it is present at limited sites in the brain including the reward pathway. Lynx1 modulates several nAChR subtypes; lynx1-nAChR interaction sites could possibly provide drug targets. We found that dopaminergic cells from the substantia nigra pars compacta (SNc) express lynx1 mRNA transcripts and, as assessed by co-immunoprecipitation, α6 receptors form stable complexes with lynx1 protein, although co-transfection with lynx1 did not affect nicotine-induced currents from cell lines transfected with α6 and β2. To test whether lynx1 is important for the function of α6 nAChRs in vivo, we bred transgenic mice carrying a hypersensitive mutation in the α6 nAChR subunit (α6L9′S) with lynx1 knockout mice, providing a selective probe of the effects of lynx1 on α6* nAChRs. Lynx1 removal reduced the α6 component of nicotine-mediated rubidium efflux and dopamine (DA) release from synaptosomal preparations with no effect on numbers of α6β2 binding sites, indicating that lynx1 is functionally important for α6* nAChR activity. No effects of lynx1 removal were detected on nicotine-induced currents in slices from SNc, suggesting that lynx1 affects presynaptic α6* nAChR function more than somatic function. In the absence of agonist, lynx1 removal did not alter DA release in dorsal striatum as measured by fast scan cyclic voltammetry. Lynx1 removal affected some behaviors, including a novel-environment assay and nicotine-stimulated locomotion. Trends in 24-hour home-cage behavior were also suggestive of an effect of lynx1 removal. Conditioned place preference for nicotine was not affected by lynx1 removal. The results show that some functional and behavioral aspects of α6-nAChRs are modulated by lynx1.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1371/journal.pone.0188715DOIArticle
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188715PublisherArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2017 Parker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: June 14, 2017; Accepted: November 13, 2017; Published: December 5, 2017. Data Availability Statement: All relevant data are within the paper. This research was supported by funds provided by California Tobacco-Related Diseases Research Program (http://www.trdrp.org), Grant 22DT-0008 to RLP, and 19KT-0032 to JMM. Additional support was provided by NIH / NIDA (https://www.drugabuse.gov/) grants, DA003194, DA012242, and P30-DA015663 to MJM, DA017279 to HAL, and DA019375 to HAL and MJM, DA030396 and DA035942 to RMD, and DA033831, DA032464 to JMM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist. We thank J. Michael McIntosh (University of Utah, Salt Lake City, Utah) for providing α-CtxMII. WE thank Kenneth J. Kellar (Georgetown University, Washington DC) for providing 6-I-epibatidine. We thank Xiomara Perez (Center for Health Sciences, SRI International, Menlo Park, CA) for help with electrochemistry, Andrew Steele (Department of Biological Sciences, California State Polytechnic University, Pomona, CA) for help with automated behavior analyses, and Sreelaxmi Varkala for help with other behavioral analyses. Author Contributions: Conceptualization: Rell L. Parker, Ryan M. Drenan, Michael J. Marks, Julie M. Miwa, Sharon R. Grady, Henry A. Lester. Data curation: Rell L. Parker, Michael J. Marks, Sharon R. Grady. Formal analysis: Rell L. Parker, Heidi C. O'Neill, Beverley M. Henley, Michael J. Marks, Sharon R. Grady, Henry A. Lester. Funding acquisition: Rell L. Parker, Ryan M. Drenan, Julie M. Miwa. Investigation: Rell L. Parker, Heidi C. O'Neill, Beverley M. Henley, Charles R. Wageman, Ryan M. Drenan, Michael J. Marks, Julie M. Miwa, Sharon R. Grady. Methodology: Rell L. Parker, Heidi C. O'Neill, Ryan M. Drenan, Michael J. Marks, Julie M. Miwa, Sharon R. Grady, Henry A. Lester. Project administration: Henry A. Lester. Resources: Ryan M. Drenan, Henry A. Lester. Supervision: Henry A. Lester. Visualization: Henry A. Lester. Writing ± original draft: Rell L. Parker, Heidi C. O'Neill, Beverley M. Henley, Ryan M. Drenan, Michael J. Marks, Julie M. Miwa, Sharon R. Grady, Henry A. Lester. Writing ± review & editing: Rell L. Parker, Heidi C. O'Neill, Ryan M. Drenan, Michael J. Marks, Julie M. Miwa, Sharon R. Grady, Henry A. Lester.
Funders:
Funding AgencyGrant Number
California Tobacco-Related Disease Research Program22DT-0008
California Tobacco-Related Disease Research Program19KT-0032
NIHDA003194
NIHDA012242
NIHP30-DA015663
NIHDA017279
NIHDA019375
NIHDA030396
NIHDA035942
NIHDA033831
NIHDA032464
Issue or Number:12
Record Number:CaltechAUTHORS:20171211-155148787
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20171211-155148787
Official Citation:Parker RL, O'Neill HC, Henley BM, Wageman CR, Drenan RM, Marks MJ, et al. (2017). Deletion of lynx1 reduces the function of α6* nicotinic receptors. PLoS ONE 12(12): e0188715. https://doi.org/10.1371/journal.pone.0188715
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:83816
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:12 Dec 2017 21:48
Last Modified:03 Oct 2019 19:11

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