The β and α2δ auxiliary subunits of voltage-gated calcium channel 1 (Ca v 1) are required for T H 2 lymphocyte function and acute allergic airway inflammation

J Allergy Clin Immunol. 2018 Sep;142(3):892-903.e8. doi: 10.1016/j.jaci.2017.09.045. Epub 2017 Nov 10.

Abstract

Background: T lymphocytes express not only cell membrane ORAI calcium release-activated calcium modulator 1 but also voltage-gated calcium channel (Cav) 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 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 Cavβ antisense oligonucleotides to knock down 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. Cavβ antisense reduces T-cell receptor-driven calcium responses and cytokine production by mouse and human TH2 cells with no effect on TH1 cells. Cavβ is mainly involved in restraining Cav1.2 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 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 Cavβ antisense and gabapentin in allergic airway inflammation.

Keywords: Asthma; T(H)2; calcium; cytokines; voltage-gated calcium channel 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Allergens
  • Animals
  • Calcium Channels, L-Type / immunology*
  • Female
  • Hypersensitivity / immunology*
  • Inflammation / immunology
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Ovalbumin
  • Protein Subunits / immunology*
  • T-Lymphocytes / immunology*

Substances

  • Allergens
  • Calcium Channels, L-Type
  • L-type calcium channel alpha(1C)
  • Protein Subunits
  • Ovalbumin