Department of Environmental Health and Engineering, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205;
Department of Environmental Health and Engineering, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205.
Proc Natl Acad Sci U S A. 2020 Nov 10;117(45):28485-28495. doi: 10.1073/pnas.2003111117. Epub 2020 Oct 23.
The recent discovery of sensory (tastant and odorant) G protein-coupled receptors on the smooth muscle of human bronchi suggests unappreciated therapeutic targets in the management of obstructive lung diseases. Here we have characterized the effects of a wide range of volatile odorants on the contractile state of airway smooth muscle (ASM) and uncovered a complex mechanism of odorant-evoked signaling properties that regulate excitation-contraction (E-C) coupling in human ASM cells. Initial studies established multiple odorous molecules capable of increasing intracellular calcium ([Ca]) in ASM cells, some of which were (paradoxically) associated with ASM relaxation. Subsequent studies showed a terpenoid molecule (nerol)-stimulated OR2W3 caused increases in [Ca] and relaxation of ASM cells. Of note, OR2W3-evoked [Ca] mobilization and ASM relaxation required Ca flux through the store-operated calcium entry (SOCE) pathway and accompanied plasma membrane depolarization. This chemosensory odorant receptor response was not mediated by adenylyl cyclase (AC)/cyclic nucleotide-gated (CNG) channels or by protein kinase A (PKA) activity. Instead, ASM olfactory responses to the monoterpene nerol were predominated by the activity of Ca-activated chloride channels (TMEM16A), including the cystic fibrosis transmembrane conductance regulator (CFTR) expressed on endo(sarco)plasmic reticulum. These findings demonstrate compartmentalization of Ca signals dictates the odorant receptor OR2W3-induced ASM relaxation and identify a previously unrecognized E-C coupling mechanism that could be exploited in the development of therapeutics to treat obstructive lung diseases.
最近在人类支气管平滑肌上发现了感觉（味觉和气味）G 蛋白偶联受体，这表明在阻塞性肺疾病的治疗中存在未被重视的治疗靶点。在这里，我们描述了广泛的挥发性气味物质对气道平滑肌（ASM）收缩状态的影响，并揭示了一种复杂的气味诱发信号特性机制，该机制调节人 ASM 细胞的兴奋-收缩（E-C）偶联。最初的研究确定了多种能够增加 ASM 细胞内钙离子浓度([Ca])的有气味分子，其中一些（矛盾的是）与 ASM 松弛有关。随后的研究表明，萜烯分子（橙花醇）刺激 OR2W3 引起 [Ca]增加和 ASM 细胞松弛。值得注意的是，OR2W3 诱发的 [Ca]动员和 ASM 松弛需要通过储存操作钙进入（SOCE）途径的钙通量，并伴有质膜去极化。这种化学感觉气味受体反应不是由腺苷酸环化酶（AC）/环核苷酸门控（CNG）通道或蛋白激酶 A（PKA）活性介导的。相反，ASM 对单萜橙花醇的嗅觉反应主要由钙激活氯离子通道（TMEM16A）的活性介导，包括内质网（endo(sarco)plasmic reticulum）上表达的囊性纤维化跨膜电导调节因子（CFTR）。这些发现表明，钙信号的区室化决定了气味受体 OR2W3 诱导的 ASM 松弛，并确定了一种以前未被识别的 E-C 偶联机制，可用于开发治疗阻塞性肺疾病的疗法。
