Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA.
Am J Physiol Lung Cell Mol Physiol. 2012 Oct 15;303(8):L661-8. doi: 10.1152/ajplung.00075.2012. Epub 2012 Aug 24.
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.
我们的实验室之前曾报道过，支气管上皮细胞（BEC）表达经典神经递质和受体的调节级联，这些递质和受体以几乎类似神经元的方式相互作用，以实现生理调节。在本文中，我们表明，神经元中神经递质信号传递与 BEC 之间的相似性扩展到了递质受体变构调节剂的水平。Lynx1 是 ly-6/三指超家族蛋白的成员，其中许多蛋白调节受体信号转导活性。Lynx1 已被证明通过改变受体敏感性和脱敏性来调节神经元中的烟碱型乙酰胆碱受体（nAChR）功能。我们现在报告 Lynx1 在 BEC 中与 α7 nAChR 形成复合物，并作为负调节 α7 下游信号事件。用尼古丁处理 BEC 的原代培养物会增加 nAChR 亚基的水平，而 Lynx1 敲低会增强这种增加。Lynx1 敲低还增强了尼古丁诱导的 GABA(A)受体（GABA(A)R）和 MUC5AC mRNA 表达的增加，并且该效应被 α7 拮抗剂和 α7 敲低阻断。与 nAChR、GABA(A)R 和粘蛋白 mRNA 水平的增加平行，Lynx1 敲低还增加了 p-Src 的水平。与此一致，Src 信号抑制阻断了 Lynx1 敲低增加基础和尼古丁刺激的 GABA(A)R 和粘蛋白 mRNA 表达的能力。因此，Lynx1 似乎通过抑制 Src 激活来充当 α7 nAChR 诱导事件的负调节剂。这表明 Lynx1 激动剂或模拟物是开发以增加粘蛋白表达为特征的与吸烟相关疾病的新疗法的潜在重要治疗靶标。
