Parker, Rell L. and O'Neill, Heidi and Henley, Beverley 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). e0188715. ISSN 1932-6203

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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
Keywords:	Animals; Receptors; Nicotinic - physiology; Humans; RNA; Messenger - genetics; HEK293 Cells; Mice, Transgenic; Mice, Neurons - metabolism; Dopamine - metabolism; GPI-Linked Proteins - genetics; Bioengineering; Brain; Immunoprecipitation; Hyperactivity; Substantia nigra; Biology; Rubidium; Proteins; Receptors; Transfection; Clonal deletion; Rodents; Neostriatum; Reinforcement; Deletion; Behavior; Conditioning; Dopamine receptors; Neurochemistry; Efflux; Dopamine; Transgenic mice; Studies; Locomotion; Addiction; Cell lines; Acetylcholine receptors (nicotinic); In vivo methods and tests; Acetylcholine; Mutation; Receptor mechanisms; Binding sites; Nicotine;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	11562
Identification Number:	https://doi.org/10.1371/journal.pone.0188715
Depositing User:	Beverley Henley
Date Deposited:	01 Nov 2019 16:33
Journal or Publication Title:	PLoS ONE
Publisher:	Public Library of Science
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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