A role for the adhesion G-protein coupled receptor ADGRE2 or EMR2 in mechanosensing was revealed by the finding of a missense substitution (p.C492Y) associated with familial vibratory urticaria. In these patients, friction of the skin induces mast cell hyper-degranulation through p.C492Y-ADGRE2, causing localized hives, flushing, and hypotension. We have now characterized the responses and intracellular signals elicited by mechanical activation in human mast cells expressing p.C492Y-ADGRE2 and attached to dermatan sulfate, a ligand for ADGRE2. The presence of p.C492Y-ADGRE2 reduced the threshold to activation and increased the extent of degranulation along with the percentage of mast cells responding. Vibration caused phospholipase C activation, transient increases in cytosolic calcium, and downstream activation of phosphoinositide 3-kinase and extracellular signal–regulated kinases 1 and 2 by Gβγ, Gα_q/11, and Gα_i/o-independent mechanisms. Degranulation induced by vibration was dependent on phospholipase C pathways, including calcium, protein kinase C, and phosphoinositide 3-kinase but not extracellular signal–regulated kinases 1/2 pathways, along with pertussis toxin-sensitive signals. In addition, mechanoactivation of mast cells stimulated the synthesis and release of prostaglandin D₂, to our knowledge a previously unreported mediator in vibratory urticaria, and extracellular signal–regulated kinases 1/2 activation was required for this response together with calcium, protein kinase C, and to some extent, phosphoinositide 3-kinase. Our studies thus identified critical molecular events initiated by mechanical forces and potential therapeutic targets for patients with vibratory urticaria.

通过发现与家族性振动性荨麻疹相关的错义取代 (p.C492Y)，揭示了粘附 G 蛋白偶联受体 ADGRE2 或 EMR2 在机械传感中的作用。在这些患者中，皮肤摩擦通过 p.C492Y-ADGRE2 诱导肥大细胞过度脱颗粒，导致局部荨麻疹、潮红和低血压。我们现在已经表征了表达 p.C492Y-ADGRE2 并附着于硫酸皮肤素（ADGRE2 的配体）的人肥大细胞中机械激活引起的反应和细胞内信号。 p.C492Y-ADGRE2 的存在降低了激活阈值，并增加了脱粒程度以及肥大细胞响应的百分比。振动导致磷脂酶 C 激活、胞质钙瞬时增加，以及通过 Gβγ、Gα _q/11和 Gα _i/o独立机制下游磷酸肌醇 3 激酶和细胞外信号调节激酶 1 和 2 的激活。振动诱导的脱颗粒依赖于磷脂酶 C 途径，包括钙、蛋白激酶 C 和磷酸肌醇 3-激酶，但不依赖于细胞外信号调节激酶 1/2 途径，以及百日咳毒素敏感信号。此外，肥大细胞的机械激活刺激了前列腺素 D ₂的合成和释放，据我们所知，前列腺素 D 2 是振动性荨麻疹中以前未报道的介质，并且这种反应需要细胞外信号调节激酶 1/2 激活以及钙、蛋白激酶 C ，并在某种程度上，磷酸肌醇3-激酶。因此，我们的研究确定了机械力引发的关键分子事件和振动性荨麻疹患者的潜在治疗靶点。