Ion channelopathies of the immune system

Abstract

Ion channels and transporters move ions across membrane barriers and are essential for a host of cell functions in many organs. They conduct K⁺, Na⁺ and Cl^-, which are essential for regulating the membrane potential, H⁺ to control intracellular and extracellular pH and divalent cations such as Ca²⁺, Mg²⁺ and Zn²⁺, which function as second messengers and cofactors for many proteins. Inherited channelopathies due to mutations in ion channels or their accessory proteins cause a variety of diseases in the nervous, cardiovascular and other tissues, but channelopathies that affect immune function are not as well studied. Mutations in ORAI1 and STIM1 genes that encode the Ca²⁺ release-activated Ca²⁺ (CRAC) channel in immune cells, the Mg²⁺ transporter MAGT1 and the Cl^- channel LRRC8A all cause immunodeficiency with increased susceptibility to infection. Mutations in the Zn²⁺ transporters SLC39A4 (ZIP4) and SLC30A2 (ZnT2) result in nutritional Zn²⁺ deficiency and immune dysfunction. These channels, however, only represent a fraction of ion channels that regulate immunity as demonstrated by immune dysregulation in channel knockout mice. The immune system itself can cause acquired channelopathies that are associated with a variety of diseases of nervous, cardiovascular and endocrine systems resulting from autoantibodies binding to ion channels. These autoantibodies highlight the therapeutic potential of functional anti-ion channel antibodies that are being developed for the treatment of autoimmune, inflammatory and other diseases.

Figure 1. Mutations interfering with the function or expression of ion channels (ORAI1, STIM1, LRRC8A) or transporters (MAGT1) in T cells cause channelopathies and immunodeficiency

T cell receptor (TCR) stimulation activates the kinases Lck and ZAP-70 and phospholipase Cγ1, resulting in the hydrolysis of PIP₂ into the second messengers inositol-1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ binding to IP₃ receptor channels leads to Ca²⁺ release from the endoplasmic reticulum (ER). The decrease in the ER Ca²⁺ concentration ([Ca²⁺]_ER) activates stromal interaction molecules 1 (STIM1) and STIM2, which subsequently bind to and open Ca²⁺ release-activated Ca²⁺ (CRAC) channels formed by ORAI1 and ORAI2 proteins in the PM. The resulting influx of extracellular Ca²⁺ is called store-operated Ca²⁺ entry (SOCE). Free cytosolic Ca²⁺ is pumped back into ER Ca²⁺ stores by the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). LoF mutations in ORAI1 or STIM1 genes cause CRAC channelopathy with impaired T and NK cell function. TCR stimulation also activates the Mg²⁺ transporter (MAGT1) that mediates Mg²⁺ influx into T cells and promotes activation of PLCγ1, SOCE and expression of NKG2D. The mechanisms by which TCR stimulation activates MGAT1 and how Mg²⁺ causes PLCγ1 activation are not well understood (indicated by question marks). LoF mutations in the MAGT1 gene cause X-linked immunodeficiency with Mg²⁺ defect, EBV infection and neoplasia (XMEN) disease. LRRC8A is a volume-regulated anion channel (VRAC) that conducts Cl⁻ and is required for the regulatory volume decrease after cell swelling as well as T and B cell development. LoF mutations in LRRC8A cause agammaglobulinemia. For details see text.