The β and α2δ auxiliary subunits of voltage-gated calcium channel 1 (Ca_v1) are required for T_H2 lymphocyte function and acute allergic airway inflammation.

Abstract

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 α1 and auxiliary subunits (β and α2δ) needed for proper trafficking and activation of the channel. Previously, we disclosed the role of Ca_v1.2 α1 in mouse and human T_H2 but not T_H1 cell functions and showed that knocking down Ca_v1 α1 prevents experimental asthma. We investigated the role of β and α2δ auxiliary subunits on Ca_v1 α1 function in T_H2 lymphocytes and on the development of acute allergic airway inflammation. We used Ca_vβ antisense oligonucleotides to knock down Ca_vβ and gabapentin, a drug that binds to and inhibits α2δ1 and α2δ2, to test their effects on T_H2 functions and their capacity to reduce allergic airway inflammation. Mouse and human T_H2 cells express mainly Ca_vβ1, β3, and α2δ2 subunits. Ca_vβ antisense reduces T-cell receptor-driven calcium responses and cytokine production by mouse and human T_H2 cells with no effect on T_H1 cells. Ca_vβ is mainly involved in restraining Ca_v1.2 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 T_H2 cells. These results stress the role of Ca_vβ and α2δ2 auxiliary subunits in the stability and activation of Ca_v1.2 channels in T_H2 lymphocytes both in vitro and in vivo, as demonstrated by the beneficial effect of Ca_vβ antisense and gabapentin in allergic airway inflammation.