The beta and alpha 2 delta auxiliary subunits of voltage-gated Check updates calcium channel 1 (Ca(v)1) are required for T(H)2 lymphocyte function and acute allergic airway inflammation

Background: T lymphocytes express not only cell membrane ORAI calcium release activated calcium modulator 1 but also voltage-gated calcium channel (Ca-v) 1 channels In excitable cells these channels are composed of the ion-forming pore al and auxiliary subunits (beta and alpha 2 delta) needed for proper trafficking and activation of the channel. Previously, we disclosed the role of Ca(v)1.2 alpha 1 in mouse and human T(H)2 but not T(H)1 cell functions and showed that knocking down Cav(1) al prevents experimental asthma. Objective: We investigated the role of beta and alpha 2 delta auxiliary subunits on Ca(v)1 alpha 1 function in T(H)2 lymphocytes and on the development of acute allergic airway inflammation. Methods: We used Ca-v beta antisense oligonucleotides to knock down Ca-v beta and gabapentin, a drug that binds to and inhibits alpha 2 delta 1 and alpha 2 delta 2, to test their effects on T(H)2 functions and their capacity to reduce allergic airway inflammation. Results: Mouse and human T(H)2 cells express mainly Ca-v beta 1, beta 3, and alpha 2 delta 2 subunits. Ca-v beta antisense reduces T-cell receptor driven calcium responses and cytokine production by mouse and human T(H)2 cells with no effect on T(H)1 cells. Ca-v beta is mainly involved in restraining Ca(v)1.2 alpha 1 degradation through the proteasome because a proteasome inhibitor partially restores the al protein level. Gabapentin impairs the T-cell receptor driven calcium response and cytokine production associated with the loss of alpha 2 delta 2 protein in T(H)2 cells. Conclusions: These results stress the role of Ca-v beta and alpha 2 delta 2 auxiliary subunits in the stability and activation of Cav1.2 channels in TH2 lymphocytes both in vitro and in vivo, as demonstrated by the beneficial effect of Cav beta antisense and gabapentin in allergic airway inflammation.