Calcium/calmodulin-dependent regulation of Rac GTPases and Akt in histamine-induced chemotaxis of mast cells
Calcium/calmodulin-dependent regulation of Rac GTPases and Akt in histamine-induced chemotaxis of mast cells
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DOI：
10.1016/j.cellsig.2021.109973
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发表时间：
2021-03-21
影响因子：
4.8
通讯作者：
Kuramasu, Atsuo
中科院分区：
文献类型：
--
作者：
Honda, Takeshi;Nishio, Yusuke;Kuramasu, Atsuo
组胺通过组胺H4受体诱导肥大细胞的趋化性。这涉及磷脂酰肌醇-4，5-二磷酸3-激酶（PI 3 K）下游的小GTP酶Rac 1和Rac 2的激活。H4受体的激活也导致磷脂酶C（PLC）介导的钙动员，但是，目前还不清楚PLC是否？钙通道与PI 3 K-Rac通道相互作用。在这里，我们证明，钙动员调节PI 3 K依赖性激活的Rac GTP酶通过钙调蛋白。PLC抑制剂（U 73122）和细胞内钙螯合剂（BAPTA-AM）抑制组胺诱导的Rac激活，而钙离子载体离子霉素增加活性Rac GTP酶，表明细胞内钙调节Rac的激活。钙调素拮抗剂（W-7）抑制组胺诱导的Rac活化和肥大细胞迁移，表明钙调素介导钙的作用。抑制钙/钙调蛋白信号抑制组胺诱导的Akt磷酸化。Akt抑制剂MK-2206减弱组胺诱导的肥大细胞迁移。然而，它不抑制Rac GTP酶的活化。这些结果表明，Rac GTP酶和Akt发挥独立的作用，在组胺诱导的肥大细胞的趋化性。我们的研究结果能够进一步阐明组胺诱导的肥大细胞趋化性的分子机制，并有助于确定涉及肥大细胞积聚的过敏性和炎症性疾病的治疗靶点。
Histamine induces chemotaxis of mast cells through the histamine H4 receptor. This involves the activation of small GTPases, Rac1 and Rac2, downstream of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). Activation of the H4 receptor also results in phospholipase C (PLC)-mediated calcium mobilization; however, it is unclear whether the PLC?calcium pathway interacts with the PI3K-Rac pathway. Here, we demonstrated that calcium mobilization regulates the PI3K-dependent activation of Rac GTPases through calmodulin. A PLC inhibitor (U73122) and an intracellular calcium chelator (BAPTA-AM) suppressed the histamine-induced activation of Rac, whereas the calcium ionophore ionomycin increased the active Rac GTPases, suggesting that intracellular calcium regulates the activation of Rac. The calmodulin antagonist (W-7) inhibited the histamine-induced activation of Rac and migration of mast cells, indicating that calmodulin mediates the effect of calcium. Inhibition of calcium/calmodulin signaling suppressed histamine-induced phosphorylation of Akt. The Akt inhibitor MK-2206 attenuated histamine-induced migration of mast cells. However, it did not suppress the activation of Rac GTPases. These results suggest that Rac GTPases and Akt play independent roles in the histamine-induced chemotaxis of mast cells. Our findings enable further elucidation of the molecular mechanism of histamineinduced chemotaxis of mast cells and help identify therapeutic targets for allergic and inflammatory conditions involving mast cell accumulation.