G protein-coupled receptors serve as mechanosensors for fluid shear stress in neutrophils
G protein-coupled receptors serve as mechanosensors for fluid shear stress in neutrophils
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DOI：
10.1152/ajpcell.00576.2005
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发表时间：
2006-06-01
影响因子：
5.5
通讯作者：
Schmid-Schöenbein, GW
中科院分区：
文献类型：
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作者：
Makino, A;Prossnitz, ER;Schmid-Schöenbein, GW
许多细胞对流体剪切应力作出反应，但以细胞类型特异性的方式。施加于白细胞的流体剪切应力控制假足的形成、迁移和其他功能。具体来说，来自分化的HL60细胞的新鲜中性粒细胞或中性粒细胞通过细胞质假足缩回来响应流体剪切应力。然而，感知流体剪切并诱导这种特异性反应的膜元件仍然未知。我们假设膜受体可以作为流体剪切传感器。我们发现流体剪切降低了G蛋白偶联受体（gpcr）的组成活性。反受体激动剂抑制GPCR组成活性可消除流体剪切应力诱导的细胞面积减少。在中性粒细胞中的gpcr中，甲酰基肽受体（FPR）具有较高的组成活性。缺乏FPR的未分化的HL60细胞很少形成假足，并且对流体剪切应力没有可检测到的反应，而未分化的HL60细胞中表达FPR会在流体剪切过程中引起假足投射和假足强劲收缩。FPR小干扰rna转染分化的HL60细胞对流体剪切应力无反应。这些结果表明，gpcr通过降低中性粒细胞的本构活性和减少假足投影，可以作为中性粒细胞流体剪切应力的机械传感器。
Many cells respond to fluid shear stress but in a cell type-specific fashion. Fluid shear stress applied to leukocytes serves to control pseudopod formation, migration, and other functions. Specifically, fresh neutrophils or neutrophilic leukocytes derived from differentiated HL60 cells respond to fluid shear stress by cytoplasmic pseudopod retraction. The membrane elements that sense fluid shear and induce such a specific response are still unknown, however. We hypothesized that membrane receptors may serve as fluid shear sensors. We found that fluid shear decreased the constitutive activity of G protein-coupled receptors (GPCRs). Inhibition of GPCR constitutive activity by inverse agonists abolished fluid shear stress-induced cell area reduction. Among the GPCRs in neutrophils, the formyl peptide receptor (FPR) exhibits relatively high constitutive activity. Undifferentiated HL60 cells that lacked FPR formed few pseudopods and showed no detectable response to fluid shear stress, whereas expression of FPR in undifferentiated HL60 cells caused pseudopod projection and robust pseudopod retraction during fluid shear. FPR small interfering RNA-transfected differentiated HL60 cells exhibited no response to fluid shear stress. These results suggest that GPCRs serve as mechanosensors for fluid shear stress in neutrophils by decreasing its constitutive activity and reducing pseudopod projection.