Pleiotropic Effects of Bitter Taste Receptors on [Ca2+]i Mobilization, Hyperpolarization, and Relaxation of Human Airway Smooth Muscle Cells.
Pleiotropic Effects of Bitter Taste Receptors on [Ca2+]i Mobilization, Hyperpolarization, and Relaxation of Human Airway Smooth Muscle Cells.
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DOI：
10.1371/journal.pone.0131582
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Liggett SB
中科院分区：
文献类型：
--
作者：
Camoretti-Mercado B;Pauer SH;Yong HM;Smith DC;Deshpande DA;An SS;Liggett SB
哮喘的特征在于由于局部支气管收缩物质增加而引起的人气道平滑肌（HASM）收缩引起的气道炎症和气流阻塞。我们最近在HASM上发现了苦味受体（TAS 2 Rs），其增加[Ca 2 +]i并放松肌肉。我们在这里报告，一些，但不是全部，TAS 2 R激动剂降低[Ca 2 +]i和放松HASM收缩的G蛋白偶联受体（GPCR）刺激[Ca 2 +]i。这表明TAS 2 R松弛的第二途径，以及应答表型的异质性。我们在培养的HASM细胞中使用了八种TAS 2 R激动剂和五种促收缩GPCR激动剂。我们发现抑制反应的异质性取决于促收缩GPCR的激活。例如，氯喹抑制组胺引起的[Ca 2 +]i增加，但不能抑制内皮素-1引起的[Ca 2 +]i增加。相反，马兜铃酸抑制[Ca 2 +]i增加内皮素-1，但不是组胺。当[Ca 2 +]i被缓激肽、血管紧张素和乙酰胆碱刺激时，发现其他二分反应。[Ca 2 +]i抑制与TAS 2 R亚型之间没有关联，Gq或Gi偶联的GPCR是否增加[Ca 2 +]i也没有关联。选定的研究揭示了[Ca 2 +]i抑制和HASM细胞膜超极化之间的相关性。为了证明生理相关性，将铁磁珠附着于HASM细胞，并通过磁扭转细胞术测量细胞刚度。与[Ca 2 +]i抑制结果一致，氯喹消除了组胺引起的细胞硬化反应（收缩），但不是内皮素-1，而马兜铃酸抑制内皮素-1引起的细胞硬化，但不是组胺。在使用完整的人支气管的研究中，发现了这些相同的差异反应。这些TAS 2 R激动剂降低[Ca 2 +]i，促进超极化，降低HASM硬度，导致人气道松弛。因此，TAS 2 R以两种方式放松HASM：低效率的从头[Ca 2 +]i刺激，以及对GPCR刺激的[Ca 2 +]i的高效抑制。此外，TAS 2 R和一些GPCR之间存在相互作用，促进了这种[Ca 2 +]i抑制分支。
Asthma is characterized by airway inflammation and airflow obstruction from human airway smooth muscle (HASM) constriction due to increased local bronchoconstrictive substances. We have recently found bitter taste receptors (TAS2Rs) on HASM, which increase [Ca2+]i and relax the muscle. We report here that some, but not all, TAS2R agonists decrease [Ca2+]i and relax HASM contracted by G-protein coupled receptors (GPCRs) that stimulate [Ca2+]i. This suggests both a second pathway by which TAS2Rs relax, and, a heterogeneity of the response phenotype. We utilized eight TAS2R agonists and five procontractile GPCR agonists in cultured HASM cells. We find that heterogeneity in the inhibitory response hinges on which procontractile GPCR is activated. For example, chloroquine inhibits [Ca2+]i increases from histamine, but failed to inhibit [Ca2+]i increases from endothelin-1. Conversely, aristolochic acid inhibited [Ca2+]i increases from endothelin-1 but not histamine. Other dichotomous responses were found when [Ca2+]i was stimulated by bradykinin, angiotensin, and acetylcholine. There was no association between [Ca2+]i inhibition and TAS2R subtype, nor whether [Ca2+]i was increased by Gq- or Gi-coupled GPCRs. Selected studies revealed a correlation between [Ca2+]i inhibition and HASM cell-membrane hyperpolarization. To demonstrate physiologic correlates, ferromagnetic beads were attached to HASM cells and cell stiffness measured by magnetic twisting cytometry. Consistent with the [Ca2+]i inhibition results, chloroquine abolished the cell stiffening response (contraction) evoked by histamine but not by endothelin-1, while aristolochic acid inhibited cell stiffening from endothelin-1, but not from histamine. In studies using intact human bronchi, these same differential responses were found. Those TAS2R agonists that decreased [Ca2+]i, promoted hyperpolarization, and decreased HASM stiffness, caused relaxation of human airways. Thus TAS2Rs relax HASM in two ways: a low-efficiency de novo [Ca2+]i stimulation, and, a high-efficiency inhibition of GPCR-stimulated [Ca2+]i. Furthermore, there is an interaction between TAS2Rs and some GPCRs that facilitates this [Ca2+]i inhibition limb.
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气道平滑肌上的苦味受体通过局部钙信号传导和反向阻塞来支气管扩张。
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
6.7
作者：
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通讯作者：
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影响因子：
4.2
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通讯作者：
Lipworth, BJ
影响因子：
5.6
作者：
Hohendanner F;McCulloch AD;Blatter LA;Michailova AP
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Michailova AP