Center of Physiopathology Toulouse Purpan, University Paul Sabatier Toulouse III, INSERM U1043, CNRS UMR 5282, Toulouse, France.
Institut du Thorax, INSERM CNRS, UNIV Nantes, France.
J Allergy Clin Immunol. 2018 Sep;142(3):892-903.e8. doi: 10.1016/j.jaci.2017.09.045. Epub 2017 Nov 10.
T lymphocytes express not only cell membrane ORAI calcium release-activated calcium modulator 1 but also voltage-gated calcium channel (Ca) 1 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. Previously, we disclosed the role of Ca1.2 α1 in mouse and human T2 but not T1 cell functions and showed that knocking down Ca1 α1 prevents experimental asthma.
We investigated the role of β and α2δ auxiliary subunits on Ca1 α1 function in T2 lymphocytes and on the development of acute allergic airway inflammation.
We used Caβ antisense oligonucleotides to knock down Caβ and gabapentin, a drug that binds to and inhibits α2δ1 and α2δ2, to test their effects on T2 functions and their capacity to reduce allergic airway inflammation.
Mouse and human T2 cells express mainly Caβ1, β3, and α2δ2 subunits. Caβ antisense reduces T-cell receptor-driven calcium responses and cytokine production by mouse and human T2 cells with no effect on T1 cells. Caβ is mainly involved in restraining Ca1.2 α1 degradation through the proteasome because a proteasome inhibitor partially restores the α1 protein level. Gabapentin impairs the T-cell receptor-driven calcium response and cytokine production associated with the loss of α2δ2 protein in T2 cells.
These results stress the role of Caβ and α2δ2 auxiliary subunits in the stability and activation of Ca1.2 channels in T2 lymphocytes both in vitro and in vivo, as demonstrated by the beneficial effect of Caβ antisense and gabapentin in allergic airway inflammation.
T 淋巴细胞不仅表达细胞膜 ORAI 钙释放激活钙调制器 1，还表达电压门控钙通道（Ca）1 通道。在可兴奋细胞中，这些通道由形成孔的 α1 离子和辅助亚基（β 和 α2δ）组成，这些亚基对于通道的正确转运和激活是必需的。此前，我们揭示了 Ca1.2α1 在小鼠和人类 T2 但不是 T1 细胞功能中的作用，并表明敲低 Ca1α1 可预防实验性哮喘。
我们研究了辅助亚基 Caβ 和 α2δ 在 T2 淋巴细胞中 Ca1α1 功能以及在急性过敏性气道炎症发展中的作用。
我们使用 Caβ 反义寡核苷酸敲低 Caβ，并使用加巴喷丁（一种与 α2δ1 和 α2δ2 结合并抑制其功能的药物）来测试其对 T2 功能的影响及其降低过敏性气道炎症的能力。
小鼠和人类 T2 细胞主要表达 Caβ1、β3 和 α2δ2 亚基。Caβ 反义寡核苷酸降低了 TCR 驱动的钙反应和细胞因子产生，而对 T1 细胞没有影响。Caβ 主要通过蛋白酶体来抑制 Ca1.2α1 的降解，因为蛋白酶体抑制剂可部分恢复α1 蛋白水平。加巴喷丁损害 TCR 驱动的钙反应和细胞因子产生，同时 T2 细胞中 α2δ2 蛋白丢失。
这些结果强调了 Caβ 和 α2δ2 辅助亚基在 T2 淋巴细胞中 Ca1.2 通道的稳定性和激活中的作用，这在体外和体内均得到了 Caβ 反义寡核苷酸和加巴喷丁在过敏性气道炎症中的有益作用的证实。
