Vennekens Rudi, Olausson Jenny, Meissner Marcel, Bloch Wilhelm, Mathar Ilka, Philipp Stephan E, Schmitz Frank, Weissgerber Petra, Nilius Bernd, Flockerzi Veit, Freichel Marc
Laboratory of Ion Channel Research, Division of Physiology, Department of Molecular Cell Biology, Campus Gasthuisberg, O&N1, KU Leuven, Herestraat 49 bus 802, B-3000 Leuven, Belgium.
Nat Immunol. 2007 Mar;8(3):312-20. doi: 10.1038/ni1441. Epub 2007 Feb 11.
Mast cells are key effector cells in allergic reactions. Aggregation of the receptor FcepsilonRI in mast cells triggers the influx of calcium (Ca(2+)) and the release of inflammatory mediators. Here we show that transient receptor potential TRPM4 proteins acted as calcium-activated nonselective cation channels and critically determined the driving force for Ca(2+) influx in mast cells. Trpm4(-/-) bone marrow-derived mast cells had more Ca(2+) entry than did TRPM4(+/+) cells after FcepsilonRI stimulation. Consequently, Trpm4(-/-) bone marrow-derived mast cells had augmented degranulation and released more histamine, leukotrienes and tumor necrosis factor. Trpm4(-/-) mice had a more severe IgE-mediated acute passive cutaneous anaphylactic response, whereas late-phase passive cutaneous anaphylaxis was not affected. Our results establish the physiological function of TRPM4 channels as critical regulators of Ca(2+) entry in mast cells.
肥大细胞是过敏反应中的关键效应细胞。肥大细胞中FcepsilonRI受体的聚集会触发钙（Ca(2+)）内流并释放炎症介质。在此我们表明，瞬时受体电位TRPM4蛋白作为钙激活的非选择性阳离子通道，关键地决定了肥大细胞中Ca(2+)内流的驱动力。FcepsilonRI刺激后，Trpm4(-/-)骨髓来源的肥大细胞比TRPM4(+/+)细胞有更多的Ca(2+)内流。因此，Trpm4(-/-)骨髓来源的肥大细胞脱颗粒增加，释放更多的组胺、白三烯和肿瘤坏死因子。Trpm4(-/-)小鼠有更严重的IgE介导的急性被动皮肤过敏反应，而迟发性被动皮肤过敏反应不受影响。我们的结果确立了TRPM4通道作为肥大细胞中Ca(2+)内流关键调节因子的生理功能。
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