BACKGROUND: T-lymphocytes express not only the cell membrane calcium ORAI1 but also voltage-dependent Cav1 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 Cav1.2 α1 in mouse and human Th2- but not Th1-cell functions and showed that knocking-down Cav1 α1 prevents experimental asthma OBJECTIVE: We investigated the role of β and α2δ auxiliary subunits on Cav1 α1 function in Th2 lymphocytes and on the development of acute allergic airway inflammation. METHODS: We used antisense oligonucleotides (CavβAS) to knockdown Cavβ 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 Cavβ1, β3 and α2δ2 subunits. CavβAS reduces TCR-driven calcium responses and cytokine production by mouse and human Th2, with no effect on Th1-cells. Cavβ is mainly involved in restraining Cav1.2 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 Cavβ and α2δ2 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 CavβAS and gabapentin in allergic airway inflammation. CLINICAL IMPLICATIONS: The demonstration that auxiliary subunits are involved in calcium signaling through Cav1 channels and function of mouse and human Th2-lymphocytes supports their potential beneficial effect on allergic asthma.