The β and α2δ auxiliary subunits of voltage-gated calcium channel 1 (Ca1) are required for T2 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) 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.