The CaV1.4 Calcium Channel Is a Critical Regulator of T Cell Receptor Signaling and Naive T Cell Homeostasis

Abstract

The transport of calcium ions (Ca(2+)) to the cytosol is essential for immunoreceptor signaling, regulating lymphocyte differentiation, activation, and effector function. Increases in cytosolic-free Ca(2+) concentrations are thought to be mediated through two interconnected and complementary mechanisms: the release of endoplasmic reticulum Ca(2+) "stores" and "store-operated" Ca(2+) entry via plasma membrane channels. However, the identity of molecular components conducting Ca(2+) currents within developing and mature T cells is unclear. Here, we have demonstrated that the L-type "voltage-dependent" Ca(2+) channel Ca(V)1.4 plays a cell-intrinsic role in the function, development, and survival of naive T cells. Plasma membrane Ca(V)1.4 was found to be essential for modulation of intracellular Ca(2+) stores and T cell receptor (TCR)-induced rises in cytosolic-free Ca(2+), impacting activation of Ras-extracellular signal-regulated kinase (ERK) and nuclear factor of activated T cells (NFAT) pathways. Collectively, these studies revealed that Ca(V)1.4 functions in controlling naive T cell homeostasis and antigen-driven T cell immune responses.

Bioinformatics Analysis of Proteome Changes in Calu-3 Cell Infected by Influenza A Virus (H5N1)

“…Another protein, NCKX6, is a member the family of potassium-dependent sodium/calcium exchangers that contribute to sustain cellular calcium homeostasis [Guerini et al, 2005]. It was demonstrated that the transportation of calcium ions (Ca 2+ ) to the cytosol is necessary for immune-receptor signaling, mediating lymphocyte activation, differentiation and effector function [Carafoli, 1987;Omilusik et al, 2011]. Interestingly, it was found TCR caused increased cytosolic-free Ca 2+ , and then impacted activation of nuclear factor and Ras-extracellular signal-regulated kinase of activated T-cell pathways [Omilusik et al, 2011].…”

“…It was demonstrated that the transportation of calcium ions (Ca 2+ ) to the cytosol is necessary for immune-receptor signaling, mediating lymphocyte activation, differentiation and effector function [Carafoli, 1987;Omilusik et al, 2011]. Interestingly, it was found TCR caused increased cytosolic-free Ca 2+ , and then impacted activation of nuclear factor and Ras-extracellular signal-regulated kinase of activated T-cell pathways [Omilusik et al, 2011]. Therefore, we have found that the influenza virus might infect the host successfully with 2,156 CNEPs via regulating the host cell recognition and inorganic cation transportation.…”

Immunosuppression by N-Methyl-d-Aspartate Receptor Antagonists Is Mediated through Inhibition of Kv1.3 and KCa3.1 Channels in T Cells

“…Although CRAC channels can be activated at low membrane potential, the changed membrane potential will alter open probability and conductivity compared to the normal resting membrane potential. Therefore, the reduced Ca 2ϩ response in the presence of NMDAR antagonists is, at least partially, caused by lowering the Ca 2ϩ influx and by inhibition of the positive feedback function of Ca 2ϩ -induced activation of K Ca 3.1 channels during T-cell activation (56)(57)(58)(59)(60).…”

Calcium Channels in Fc Receptor Signaling

“…Recently, it has been suggested that voltage-gated Ca 2+ channels might play a different role in T cell biology than CRAC channels (Badou et al 2013). For example Ca v 1.4 modulates naïve T cell survival and antigen-driven immune responses (Omilusik et al 2011).…”