Depression of CaV1.2 activation and expression in mast cells ameliorates allergic inflammation diseases.

Journal of pharmaceutical analysis Pub Date : 2024-11-01 Epub Date: 2024-11-14 DOI:10.1016/j.jpha.2024.101149
Yongjing Zhang, Yingnan Zeng, Haoyun Bai, Wen Zhang, Zhuoyin Xue, Shiling Hu, Shemin Lu, Nan Wang
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Abstract

Allergic inflammation is closely related to the activation of mast cells (MCs), which is regulated by its intracellular Ca2+ level, but the intake and effects of the intracellular Ca2+ remain unclear. The Ca2+ influx is controlled by members of Ca2+ channels, among which calcium voltage-gated channel subunit alpha1 C (CaV1.2) is the most robust. This study aimed to reveal the role and underlying mechanism of MC CaV1.2 in allergic inflammation. We found that CaV1.2 participated in MC activation and allergic inflammation. Nimodipine (Nim), as a strong CaV1.2-specific antagonist, ameliorated allergic inflammation in mice. Further, CaV1.2 activation in MC was triggered by phosphatizing at its Ser1928 through protein kinase C (PKC), which calcium/calmodulin-dependent protein kinase II (CaMKII) catalyzed. Overexpression or knockdown of MC CaV1.2 influenced MC activation. Importantly, CaV1.2 expression in MC had detrimental effects, while its deficiency ameliorated allergic pulmonary inflammation. Results provide novel insights into CaV1.2 function and a potential drug target for controlling allergic inflammation.

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抑制肥大细胞中CaV1.2的激活和表达可改善变应性炎症疾病。
过敏性炎症与肥大细胞(MCs)的激活密切相关,而肥大细胞(MCs)的激活受其细胞内Ca2+水平的调节,但细胞内Ca2+的摄入及其作用尚不清楚。Ca2+内流受Ca2+通道成员控制,其中钙电压门控通道亚基α 1 C (CaV1.2)最为稳健。本研究旨在揭示mccav1.2在变应性炎症中的作用及其机制。我们发现CaV1.2参与了MC活化和过敏性炎症。尼莫地平(Nim)作为一种强cav1.2特异性拮抗剂,可改善小鼠变应性炎症。此外,MC中CaV1.2的激活是由钙/钙调素依赖性蛋白激酶II (CaMKII)催化的蛋白激酶C (PKC)在其丝氨酸1928位点磷酸化引发的。mccav1.2的过表达或敲低影响mcca1.2的活化。重要的是,CaV1.2在MC中的表达具有不利影响,而其缺乏可改善变应性肺部炎症。研究结果为CaV1.2的功能和控制变应性炎症的潜在药物靶点提供了新的见解。
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