Background

T-lymphocytes express not only the cell membrane calcium ORAI1 but also voltage-dependent Ca_v1 channels. In excitable cells, these channels are composed of the ion forming pore α1 and auxiliary subunits (β and α2δ) needed for proper trafficking and activation of the channel. We previously disclosed the role of Ca_v1.2 α1 in mouse and human Th2- but not Th1-cell functions and showed that knocking-down Ca_v1 α1 prevents experimental asthma

Objective

We investigated the role of β and α2δ auxiliary subunits on Ca_v1 α1 function in Th2 lymphocytes and on the development of acute allergic airway inflammation.

Methods

We used antisense oligonucleotides (Ca_vβAS) to knockdown Ca_vβ and gabapentin, a drug that binds to and inhibits α2δ1 and α2δ2, to test their effects on Th2 functions and their capacity to reduce allergic airway inflammation.

Results

Mouse and human Th2-cells express mainly Ca_vβ1, β3 and α2δ2 subunits. Ca_vβAS reduces TCR-driven calcium responses and cytokine production by mouse and human Th2, with no effect on Th1-cells. Ca_vβ is mainly involved in restraining Ca_v1.2 α1 degradation through the proteasome as a proteasome inhibitor partially restores the α1 protein level. Gabapentin impairs TCR-driven calcium response and cytokine production associated with the loss of α2δ2 protein in Th2-cells.

Conclusions

These results stress the role of Ca_vβ and α2δ2 auxiliary subunits in the stability and activation of Ca_v1.2 channels in Th2 lymphocytes both in vitro and in vivo as demonstrated by the beneficial effect of Ca_vβAS and gabapentin in allergic airway inflammation.

Clinical implications

The demonstration that auxiliary subunits are involved in calcium signaling through Ca_v1 channels and function of mouse and human Th2-lymphocytes supports their potential beneficial effect on allergic asthma.

中文翻译：

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Ca _v 1通道的β和α2δ辅助亚基是Th2淋巴细胞功能和急性过敏性气道炎症所必需的

背景

T淋巴细胞不仅表达细胞膜钙ORAI1，而且表达电压依赖性Ca _v 1通道。在可激发细胞中，这些通道由离子形成孔α1和适当运输和激活通道所需的辅助亚基（β和α2δ）组成。我们先前披露了Ca _v 1.2α1在小鼠和人类Th2细胞中的作用，但没有揭示Th1细胞的功能，并显示敲除Ca _v 1α1可预防实验性哮喘

客观的

我们研究了β和α2δ辅助亚基在Th2淋巴细胞中Ca _v 1α1功能以及急性过敏性气道炎症发展中的作用。

方法

我们使用反义寡核苷酸（CA _v βAS）拦截的Ca _v β和加巴喷丁，一种药物，结合并抑制α2δ1和α2δ2，以测试它们在Th2的功能和它们的能力的影响，以减少过敏性气道炎症。

结果

小鼠和人的Th2细胞表达主要是钙_v β1，β3和α2δ2亚基。的Ca _v βAS降低TCR驱动钙应答和由小鼠和人Th2细胞因子生产，具有对Th1细胞没有影响。Ca _vβ主要参与通过蛋白酶体抑制Ca _v 1.2α1降解，因为蛋白酶体抑制剂可部分恢复α1蛋白水平。加巴喷丁会损害TCR驱动的钙反应和细胞因子的产生，并与Th2细胞中α2δ2蛋白的丢失有关。

结论

这些结果强调Ca的作用_v β的Ca和在稳定性α2δ2辅助亚基和激活_v 1.2通道的Th2淋巴细胞两者在体外和体内的Ca的有益效果所证明_v βAS和加巴喷丁在过敏性气道炎症。

临床意义

辅助亚基通过Ca _v 1通道参与钙信号传导以及小鼠和人类Th2-淋巴细胞功能的证明支持了它们对过敏性哮喘的潜在有益作用。