The ly-6 protein, lynx1, is an endogenous inhibitor of nicotinic signaling in airway epithelium

Xiao Wen Fu, Stephen S. Rekow, Eliot R. Spindel

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    16 Scopus citations

    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 a7 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 GABAa receptors (GABAaR) and MUC5AC mRNA expression, and that effect was blocked by α7 antagonists and α7 knockdown. In parallel with the increases in nAChR, GABAaR, 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 GABAaR 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.

    Original languageEnglish (US)
    Pages (from-to)L661-L668
    JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
    Volume303
    Issue number8
    DOIs
    StatePublished - Jan 1 2012

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    Keywords

    • Asthma
    • Chronic obstructive pulmonary disease
    • Gaba
    • Mucus
    • Nicotine
    • Smoking

    ASJC Scopus subject areas

    • Physiology
    • Pulmonary and Respiratory Medicine
    • Physiology (medical)
    • Cell Biology

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