Format

Send to

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

The β and α2δ auxiliary subunits of voltage-gated calcium channel 1 (Cav1) are required for TH2 lymphocyte function and acute allergic airway inflammation.

Author information

1
Center of Physiopathology Toulouse Purpan, University Paul Sabatier Toulouse III, INSERM U1043, CNRS UMR 5282, Toulouse, France.
2
Institut du Thorax, INSERM CNRS, UNIV Nantes, France.
3
INRA, UR1268, BIA, Nantes, France.
4
Institut du Thorax, INSERM CNRS, UNIV Nantes, France; Centre Hospitalier Universitaire de Nantes, Service de Pneumologie, Nantes, France.
5
Center of Physiopathology Toulouse Purpan, University Paul Sabatier Toulouse III, INSERM U1043, CNRS UMR 5282, Toulouse, France. Electronic address: lucette.pelletier@inserm.fr.
6
Center of Physiopathology Toulouse Purpan, University Paul Sabatier Toulouse III, INSERM U1043, CNRS UMR 5282, Toulouse, France. Electronic address: magali.savignac@inserm.fr.

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

PMID:
29129580
DOI:
10.1016/j.jaci.2017.09.045
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science Icon for HAL archives ouvertes
Loading ...
Support Center