鞘氨醇-1-磷酸通过 S1PR3 受体激活小鼠迷走气道传入 C 纤维。
Sphingosine-1-phosphate activates mouse vagal airway afferent C-fibres via S1PR3 receptors.
机构信息
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
出版信息
J Physiol. 2019 Apr;597(7):2007-2019. doi: 10.1113/JP277521. Epub 2019 Feb 21.
KEY POINTS
Sphingosine-1-phosphate (S1P) strongly activates mouse vagal C-fibres in the airways. Airway-specific nodose and jugular C-fibre neurons express mRNA coding for the S1P receptor S1PR3. S1P activation of nodose C-fibres is inhibited by a S1PR3 antagonist. S1P activation of nodose C-fibres does not occur in S1PR3 knockout mice.
ABSTRACT
We evaluated the effect of sphingosine-1-phosphate (S1P), a lipid that is elevated during airway inflammatory conditions like asthma, for its ability to stimulate vagal afferent C-fibres in mouse lungs. Single cell RT-PCR on lung-specific vagal afferent neurons revealed that both TRPV1-expressing and TRPV1-non-expressing nodose neurons express mRNA coding for the S1P receptor S1PR3. TRPV1-expressing airway-specific jugular ganglion neurons also express S1PR3 mRNA. S1PR1 and S1PR2 mRNAs were also found to be expressed but only in a limited subset (32% and 22%, respectively) of airway-specific vagal sensory neurons; whereas S1PR4 and S1PR5 were rarely expressed. We used large scale two-photon imaging of the nodose ganglia from our ex vivo preparation isolated from Pirt-Cre;R26-GCaMP6s transgenic mice, which allows for simultaneous monitoring of calcium transients in ∼1000 neuronal cell bodies in the ganglia during tracheal perfusion with S1P (10 μM). We found that S1P in the lungs strongly activated 81.5% of nodose fibres, 70% of which were also activated by capsaicin. Single fibre electrophysiological recordings confirmed that S1P evoked action potential (AP) generation in a concentration-dependent manner (0.1-10 μM). Action potential generation by S1P in nodose C-fibres was effectively inhibited by the S1PR3 antagonist TY 52156 (10 μM). Finally, in S1PR3 knockout mice, S1P was not able to activate any of the airway nodose C-fibres analysed. These results support the hypothesis that S1P may play a role in evoking C-fibre-mediated airway sensations and reflexes that are associated with airway inflammatory diseases.
要点
鞘氨醇-1-磷酸（S1P）强烈激活气道中的小鼠迷走神经 C 纤维。气道特异性结状神经节和颈静脉 C 纤维神经元表达编码 S1P 受体 S1PR3 的 mRNA。S1PR3 拮抗剂抑制结状神经节 C 纤维对 S1P 的激活。S1PR3 基因敲除小鼠中不存在 S1P 激活结状神经节 C 纤维的情况。
摘要
我们评估了鞘氨醇-1-磷酸（S1P）的作用，S1P 是一种在哮喘等气道炎症条件下升高的脂质，以研究其刺激小鼠肺部迷走传入 C 纤维的能力。对肺特异性迷走传入神经元进行单细胞 RT-PCR 显示，表达 TRPV1 和不表达 TRPV1 的结状神经元均表达编码 S1P 受体 S1PR3 的 mRNA。表达 TRPV1 的气道特异性颈静脉神经节神经元也表达 S1PR3 mRNA。还发现 S1PR1 和 S1PR2 mRNA 也有表达，但仅在气道特异性迷走感觉神经元的有限亚群（分别为 32%和 22%）中；而 S1PR4 和 S1PR5 则很少表达。我们使用从 Pirt-Cre；R26-GCaMP6s 转基因小鼠分离的离体制备物的结状神经节的大规模双光子成像，允许在气管内灌注 S1P（10 μM）时同时监测神经节中约 1000 个神经元细胞体中的钙瞬变。我们发现，肺部的 S1P 强烈激活了 81.5%的结状纤维，其中 70%也被辣椒素激活。单纤维电生理记录证实，S1P 以浓度依赖性方式诱发动作电位（AP）产生（0.1-10 μM）。S1PR3 拮抗剂 TY 52156（10 μM）有效抑制 S1P 在结状 C 纤维中诱发的动作电位产生。最后，在 S1PR3 基因敲除小鼠中，S1P 不能激活分析的任何气道结状 C 纤维。这些结果支持 S1P 可能在诱发与气道炎症性疾病相关的 C 纤维介导的气道感觉和反射中发挥作用的假说。
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