title: The ly-6 protein, lynx1, is an endogenous inhibitor of nicotinic signaling in airway epithelium.
abstract: Our laboratory has previously reported that bronchial epithelial cells (BEC) express a regulatory cascade of classic neurotransmitters and receptors that communicate in an almost neuronal-like manner to achieve physiological regulation. In this paper we show that the similarity between neurotransmitter signaling in neurons and BEC extends to the level of transmitter receptor allosteric modulators. Lynx1 is a member of the ly-6/three-finger superfamily of proteins, many of which modulate receptor signaling activity. Lynx1 specifically has been shown to modulate nicotinic acetylcholine receptor (nAChR) function in neurons by altering receptor sensitivity and desensitization. We now report that lynx1 forms a complex with α7 nAChR in BEC and serves to negatively regulate α7 downstream signaling events. Treatment of primary cultures of BEC with nicotine increased levels of nAChR subunits and that increase was potentiated by lynx1 knockdown. Lynx1 knockdown also potentiated the nicotine-induced increase in GABA(A) receptors (GABA(A)R) and MUC5AC mRNA expression, and that effect was blocked by α7 antagonists and α7 knockdown. In parallel with the increases in nAChR, GABA(A)R, and mucin mRNA levels, lynx1 knockdown also increased levels of p-Src. Consistent with this, inhibition of Src signaling blocked the ability of the lynx1 knockdown to increase basal and nicotine-stimulated GABA(A)R and mucin mRNA expression. Thus lynx1 appears to act as a negative modulator of α7 nAChR-induced events by inhibiting Src activation. This suggests that lynx1 agonists or mimetics are a potentially important therapeutic target to develop new therapies for smoking-related diseases characterized by increased mucin expression.
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA.
authors.forename: Xiao Wen
authors.initials: XW
authors.lastname: Fu
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rekow
authors.forename: Eliot R
authors.initials: ER
authors.lastname: Spindel
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001249:Asthma / Q000276:immunology / Q000378:metabolism; D001980:Bronchi / Q000166:cytology; D002478:Cells, Cultured; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D008253:Macaca mulatta; D055271:Mucin 5AC / Q000276:immunology / Q000378:metabolism; D009538:Nicotine / Q000276:immunology / Q000378:metabolism; D018722:Nicotinic Agonists / Q000276:immunology / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011963:Receptors, GABA-A / Q000276:immunology / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000276:immunology / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D012907:Smoking / Q000276:immunology* / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D058851:GPI-Linked Proteins; D055271:Mucin 5AC; D018722:Nicotinic Agonists; D034741:RNA, Small Interfering; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D019061:src-Family Kinases