What’s Bred in the Bone: Calcium Channels in Lymphocytes

Fenninger, Franz; Jefferies, Wilfred A.

doi:10.4049/jimmunol.1800837

Cited by 17 publications

(18 citation statements)

References 113 publications

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“…Second, when activated, they cause cell depolarization, which is the driving force for Ca 2+ entry, and generate changes in the intracellular Ca 2+ concentration (10). Third, TRP channels are also found in the ER and mitochondria and function as intracellular Ca 2+ -release channels (13).…”

Section: Ligand-gated Transient Receptor Potential (Trp) Channelsmentioning

confidence: 99%

The Role of Calcium–Calcineurin–NFAT Signaling Pathway in Health and Autoimmune Diseases

et al. 2020

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Calcium (Ca 2+) is an essential signaling molecule that controls a wide range of biological functions. In the immune system, calcium signals play a central role in a variety of cellular functions such as proliferation, differentiation, apoptosis, and numerous gene transcriptions. During an immune response, the engagement of T-cell and B-cell antigen receptors induces a decrease in the intracellular Ca 2+ store and then activates store-operated Ca 2+ entry (SOCE) to raise the intracellular Ca 2+ concentration, which is mediated by the Ca 2+ release-activated Ca 2+ (CRAC) channels. Recently, identification of the two critical regulators of the CRAC channel, stromal interaction molecule (STIM) and Orai1, has broadened our understanding of the regulatory mechanisms of Ca 2+ signaling in lymphocytes. Repetitive or prolonged increase in intracellular Ca 2+ is required for the calcineurin-mediated dephosphorylation of the nuclear factor of an activated T cell (NFAT). Recent data indicate that Ca 2+-calcineurin-NFAT1 to 4 pathways are dysregulated in autoimmune diseases. Therefore, calcineurin inhibitors, cyclosporine and tacrolimus, have been used for the treatment of such autoimmune diseases as systemic lupus erythematosus and rheumatoid arthritis. Here, we review the role of the Ca 2+-calcineurin-NFAT signaling pathway in health and diseases, focusing on the STIM and Orai1, and discuss the deregulated calcium-mediated calcineurin-NFAT pathway in autoimmune diseases. Keywords: calcium, calcineurin, nuclear factor of an activated T-cell, Ca 2+ signaling, autoimmune disease Park et al. Calcium Signaling and Autoimmune Disease TABLE 1 | Role of elevated intracellular calcium (Ca 2+) levels in various cells. Cell type Effects Endothelial cells Increase vasodilation Secretory cells Increase secretion, stimulate vesicle fusion Juxtaglomerular cells Decrease secretion Parathyroid chief cells Decrease secretion Neurons Stimulate transmission, vesicle fusion, and increase neural adaptation Myocytes Increase contraction and activation of protein kinase C

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Section: Ligand-gated Transient Receptor Potential (Trp) Channelsmentioning

confidence: 99%

The Role of Calcium–Calcineurin–NFAT Signaling Pathway in Health and Autoimmune Diseases

et al. 2020

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“…Apart from the CRAC channel however, there exist numerous other Ca 2+ channels in the plasma membrane of lymphocytes that also contribute to the antigen receptor-mediated flux. Among them are the voltage-dependent Ca 2+ channels (VDCCs), which have emerged as important players in immune cells (8). VDCCs consist of the pore-forming Ca V (α1)-, the β regulatory-, and several other auxiliary subunits.…”

Section: Introductionmentioning

confidence: 99%

Mutation of an L-Type Calcium Channel Gene Leads to T Lymphocyte Dysfunction

et al. 2019

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Calcium (Ca2+) is a vital secondary messenger in T lymphocytes regulating a vast array of important events including maturation, homeostasis, activation, and apoptosis and can enter the cell through CRAC, TRP, and CaV channels. Here we describe a mutation in the L-type Ca2+ channel CaV1.4 leading to T lymphocyte dysfunction, including several hallmarks of immunological exhaustion. CaV1.4-deficient mice exhibited an expansion of central and effector memory T lymphocytes, and an upregulation of inhibitory receptors on several T cell subsets. Moreover, the sustained elevated levels of activation markers on B lymphocytes suggest that they are in a chronic state of activation. Functionally, T lymphocytes exhibited a reduced store-operated Ca2+ flux compared to wild-type controls. Finally, modifying environmental conditions by herpes virus infection exacerbated the dysfunctional immune phenotype of the CaV1.4-deficient mice. This is the first example where the mutation of a CaV channel leads to T lymphocyte dysfunction, including the upregulation of several inhibitory receptors, hallmarks of T cell exhaustion, and establishes the physiological importance of CaV channel signaling in maintaining a nimble immune system.

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“…We admit this area of research is not very clear, sometimes even controversial, mainly due to the very low abundance of NMDAR in non-neuronal cells. Nevertheless, some progress has been achieved in the characterization of the subunit composition and currents mediated by non-neuronal NMDAR, in particular in red blood cells (RBC) (Makhro et al, 2010), platelets (Kalev-Zylinska et al, 2014), lymphocytes (Fenninger and Jefferies, 2019), and hematopoietic precursors, erythroblasts (Makhro et al, 2013;Hanggi et al, 2014Hanggi et al, , 2015 and megakaryocytes (Genever et al, 1999;Kamal et al, 2015). Information on the potential physiological role of these receptors is accumulating as well, including in erythroid cells (Makhro et al, 2013(Makhro et al, , 2016, and megakaryocytes (Hitchcock et al, 2003;Green et al, 2017;Kamal et al, 2018;Hearn et al, 2020).…”

Section: Unexpected Discoveries Outside Of the Brainmentioning

confidence: 99%