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

Abstract

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

Interrelation between ROS and Ca2+ in aging and age-related diseases

“…In addition, Ca 2+ ions convey their action by binding to proteins such as CaN or CaM, which, in turn, have a wide area of function [ 40 ]. For instance, Ca 2+ is required for CaN-mediated dephosphorylation of the nuclear factor of an activated T cell (NFAT), which controls the expression of numerous genes and, thereby, processes including protein secretion, cell differentiation and immune response [ 41 ]. Moreover, binding of Ca 2+ causes allosteric changes in CaM, modifying its interaction with target proteins, including kinases or phosphatases, and thereby affecting neurotransmitter secretion, transcription factor regulation, metabolism and muscle contraction [ 42 ].…”

Calcineurin

“…The serine/threonine phosphatase calcineurin (CaN) is activated by increased intracellular calcium concentrations [ 1 – 4 ]. Along with the calmodulin-activated kinases [ 5 ], CaN directly links calcium signaling to protein phosphorylation states and plays an essential role in numerous signaling processes [ 6 ]. CaN is found in eukaryotes and is conserved from single cell organisms through to Homo sapiens [ 2 , 7 ].…”

Synthesis and Pharmacological Characterization of 2-Aminoethyl Diphenylborinate (2-APB) Derivatives for Inhibition of Store-Operated Calcium Entry (SOCE) in MDA-MB-231 Breast Cancer Cells

“…Gain-of-function or loss-of-function mutations in STIM1 or Orai1, or alterations in expression ratios of STIM and Orai isoforms as well as aberrations in other regulatory mechanisms of SOCE pathway lead to its dysfunction [ 9 , 10 , 11 ]. The disruption of SOCE has various pathophysiological implications such as muscle, immune, and neurodegenerative disorders as well as cancer [ 12 , 13 , 14 , 15 , 16 ]. Breast cancer metastasis has been linked to STIM1/Orai1-mediated Ca 2+ influx [ 17 ] and several studies also highlighted the upregulation of STIM1 and Orai1 in basal breast cancers [ 18 , 19 ].…”