Divalent cation signaling in immune cells

Abstract

Divalent cations of two alkaline earth metals Ca(2+) and Mg(2+) and the transition metal Zn(2+) play vital roles in the immune system, and several immune disorders are associated with disturbances of their function. Until recently only Ca(2+) was considered to serve as a second messenger. However, signaling roles for Mg(2+) and Zn(2+) have been recently described, leading to a reevaluation of their role as potential second messengers. We review here the roles of these cations as second messengers in light of recent advances in Ca(2+), Mg(2+), and Zn(2+) signaling in the immune system. Developing a better understanding of these signaling cations may lead to new therapeutic strategies for immune disorders.

Keywords: calcium; immune disorders; magnesium; signal transduction; zinc.

Figure 1. Divalent cations transporters

(a) Ca²⁺ transport mechanisms in immune cells. Ca²⁺ homeostasis regulation involves the PMCA, SERCA ATPases as well as the MCU and Na⁺/Ca²⁺ exchangers (NCX). SOCE is induced by released of Ca²⁺ from the ER by the IP₃R. STIM senses the store depletion and triggers the opening of the Ca²⁺ CRAC channel, ORAI. SOCE is modulated by two K⁺ permeable channels, K_Ca 1.3 and K_v 3.1 regulated by intracellular Ca²⁺ and depolarization respectively. These two channels help sustain SOCE generation by inducing hyperpolarization of the cell. Additionally, the Na⁺ permeable channel TRPM4 is gated by intracellular Ca²⁺ and reduces the Ca²⁺ mobilization. (b) Mg²⁺ transport mechanisms in immune cells. Mg²⁺ transporters include TRPM7, which have an intracellular Ser/Thr kinase domain, MAGT1, and SLC41A1/2 expressed on the PM and Mrs2 on the inner membrane of the mitochondria. (c) Zn²⁺ transport mechanisms in immune cells. Zn²⁺ transporters of the ZnT and ZIP families are expressed in various cellular compartments. Zn²⁺ homeostasis is completed by MT. Abbreviations: ChR, Chemokine receptor; DAG, Diacylglycerol; FcR, Fc receptor; TPC, Two pore channel.

Figure 2. Divalent cations effectors and functions in immune cells

(a) A broad range of functions can be rapidly deployed through Ca²⁺ signals. One major Ca²⁺ function is the regulation of gene expression involved in cell activation, differentiation and cytokine production. Ca²⁺ controls the activation of NFAT via CaM-CN, CREB and myocyte enhancer factor 2 (MEF2) via CaMK and CaM and NF-κB via PKC and CaMKII. Ca²⁺ controls exocytosis through Ca²⁺-sensitive proteins such as synaptotagmins (Syt) and Munc13. S100 proteins are Ca²⁺-binding proteins involved in the cytoskeleton organization during migration, lysosome-phagosome fusion during phagocytosis. In neutrophils, Ca²⁺ controls ROS production by NOX2 via PKC and S100 proteins (S100A8/A9). (b) In T and B cells, Mg²⁺ is regulating Ca²⁺ mobilization via SOCE, by modulating PLC-γ activation. In T cells, the TCR-induced MAGT1-dependent Mg²⁺ flux is required to activate PLC-γ1. In B cell, TRPM7 kinase domain participates in PLC-γ2 activation together with Bruton’s tyrosine kinase (BTK) in a Mg²⁺-dependent manner. (c) Zn²⁺ is involved in the recruitment of kinases such as PKC or LCK. Zn²⁺ enhances MAPK activation through inhibition of the MAPKP. Zn²⁺ controls gene expression through NF-κB and through inhibition of CN (which promotes CREB activation). In innate immune cells, Zn²⁺ binding-proteins such as MT and S100 proteins (S100A8/A9) are playing anti-microbial roles by chelating Zn²⁺. Zn²⁺ inhibits IL-6 signaling by inhibiting the activation of STAT3. Finally, Zn²⁺ regulates the cAMP pathway through the inhibition of AC or PDE.