title: Evaluation of the Nicotinic Acetylcholine Receptor-Associated Proteome at Baseline and Following Nicotine Exposure in Human and Mouse Cortex.
abstract: Nicotinic acetylcholine receptors (nAChRs) support the initiation and maintenance of smoking, but the long-term changes occurring in the protein complex as a result of smoking and the nicotine in tobacco are not known. Human studies and animal models have also demonstrated that increasing cholinergic tone increases behaviors related to depression, suggesting that the nAChR-associated proteome could be altered in individuals with mood disorders. We therefore immunopurified nAChRs and associated proteins for quantitative proteomic assessment of changes in protein-protein interactions of high-affinity nAChRs containing the β2 subunit (β2*-nAChRs) from either cortex of mice treated with saline or nicotine, or postmortem human temporal cortex tissue from tobacco-exposed and nonexposed individuals, with a further comparison of diagnosed mood disorder to control subjects. We observed significant effects of nicotine exposure on the β2*-nAChR-associated proteome in human and mouse cortex, particularly in the abundance of the nAChR subunits themselves, as well as putative interacting proteins that make up core components of neuronal excitability (Na/K ATPase subunits), presynaptic neurotransmitter release (syntaxins, SNAP25, synaptotagmin), and a member of a known nAChR protein chaperone family (14-3-3ζ). These findings identify candidate-signaling proteins that could mediate changes in cholinergic signaling via nicotine or tobacco use. Further analysis of identified proteins will determine whether these interactions are essential for primary function of nAChRs at presynaptic terminals. The identification of differences in the nAChR-associated proteome and downstream signaling in subjects with various mood disorders may also identify novel etiological mechanisms and reveal new treatment targets.
authors: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508; Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado 80303; Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309.
authors: Tristan D
authors: 0000-0001-5117-7074
authors: TD
authors: McClure-Begley
authors: Department of Psychiatry, Yale University School of Medicine , New Haven, Connecticut 06508.
authors: Irina
authors: I
authors: Esterlis
authors: W.M. Keck Biotechnology Resource Laboratory, Yale University School Medicine , New Haven, Connecticut 06509.
authors: Kathryn L
authors: KL
authors: Stone
authors: W.M. Keck Biotechnology Resource Laboratory, Yale University School Medicine, New Haven, Connecticut 06509; Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, Connecticut 06520.
authors: TuKiet T
authors: 0000-0002-4850-3462
authors: TT
authors: Lam
authors: Institute for Behavioral Genetics, University of Colorado , Boulder, Colorado 80303.
authors: Sharon R
authors: SR
authors: Grady
authors: W.M. Keck Biotechnology Resource Laboratory, Yale University School Medicine, New Haven, Connecticut 06509; Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, Connecticut 06520.
authors: Christopher M
authors: 0000-0002-0438-1395
authors: CM
authors: Colangelo
authors: Department of Neuroscience, Medical School of the University of Pennsylvania , Philadelphia, Pennsylvania 19104.
authors: Jon M
authors: JM
authors: Lindstrom
authors: Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado 80303; Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado 80309.
authors: Michael J
authors: MJ
authors: Marks
authors: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508; W.M. Keck Biotechnology Resource Laboratory, Yale University School Medicine, New Haven, Connecticut 06509.
authors: Marina R
authors: 0000-0002-4404-1280
authors: MR
authors: Picciotto
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D003367:Cotinine / Q000378:metabolism; D005260:Female; D006801:Humans; D001523:Mental Disorders / Q000378:metabolism / Q000473:pathology; D008822:Mice, Transgenic; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D020543:Proteome / Q000187:drug effects*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D012907:Smoking / Q000378:metabolism / Q000473:pathology; D014029:Tobacco Use Disorder / Q000378:metabolism / Q000473:pathology
chemical_list: D018722:Nicotinic Agonists; D020543:Proteome; D011978:Receptors, Nicotinic; D009538:Nicotine; D003367:Cotinine
keywords: addiction; cortex; depression; nicotine; nicotinic acetylcholine receptors; proteomics