General Aspects of Metal Ions as Signaling Agents in Health and Disease

Abstract

This review focuses on the current knowledge on the involvement of metal ions in signaling processes within the cell, in both physiological and pathological conditions. The first section is devoted to the recent discoveries on magnesium and calcium-dependent signal transduction-the most recognized signaling agents among metals. The following sections then describe signaling pathways where zinc, copper, and iron play a key role. There are many systems in which changes in intra- and extra-cellular zinc and copper concentrations have been linked to important downstream events, especially in nervous signal transduction. Iron signaling is mostly related with its homeostasis. However, it is also involved in a recently discovered type of programmed cell death, ferroptosis. The important differences in metal ion signaling, and its disease-leading alterations, are also discussed.

Keywords: cell signaling; ferroptosis; metal homeostasis.

Figure 1

Schematic diagrams of the representative members of mammalian (A) selective and (B) non-selective Mg²⁺ transporters.

Figure 2

(A) Schematic representation of calcium signaling in excitable cells. Voltage-gated calcium channels (VGCC) are found in the membrane of excitable cells. Other sources of calcium influx are calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate-type receptors, and transient receptor potential type C (TRPC) channels. cAMP-dependent protein kinases and the Ca²⁺calmodulin-dependent proteins play crucial roles in local signaling and synaptic plasticity. Calcium release from internal stores is mediated by inositol trisphosphate receptors (IP₃R), ryanodine receptors (RyR), and mitochondrial permeability transition pore (PTP). Ca²⁺ efflux is mediated by the plasma membrane calcium ATPase, the Na²⁺/Ca²⁺ exchanger, and the sarco-/endoplasmic reticulum calcium ATPase (SERCA) and the mitochondrial uniporter (UP). (B) Schematic representation of calcium signaling in non-excitable cells. Following the stimulation of G protein-coupled receptors, IP3 produced by phospholipase C (PLC) activates the IP3 receptor (IP3R) and triggers the depletion of ER calcium stores. The stromal interaction molecule 1(STIM1), representing Ca²⁺ sensor, and Orai, belonging to the group of store-operated calcium channels (SOCC) builds the ion-conducting transmembrane protein complex. STIM1 interacts with Orai1 to trigger SOCC opening. Then, SERCA pumps Ca²⁺ back into the ER to refill the stores with Ca²⁺. Transient receptor potential channels (TRPC) can be also activated by phospholipase C stimulation.

Figure 3

Schematic representation of the events related to the zinc signal release from zincergic synapses. After zinc influx, Zn²⁺ ions are bound by metallothionein 3 (MT-3). This protein delivers zinc to the zone where vesicles are formed. The influx of Zn²⁺ into the vesicle is catalyzed by ZnT-1 transporter. After release, Zn²⁺ appears in a synaptic cleft and diffuses through it. This phenomenon leads to the interaction of Zn²⁺ with postsynaptic N-methyl-D-aspartate glutamate receptor (NMDAR) and the influx of these ions into the postsynaptic nerve terminal. The level of Zn²⁺ in a postsynaptic neuron is regulated by the ZnT-1 transporter responsible for efflux of Zn²⁺ excess. The location of ZnT-1 in the membrane allows this transporter to interact with the GluN2A subunit of NMDAR (blue sphere).

Figure 4

The schematic representation of an example sequence of events related to copper release possible in nerve cells. Copper ions are taken up to the cell by a Cu transporter 1 (CTR-1). The presence of free Cu⁺ ions immediately activates a set of copper chaperones. These proteins transport copper within the cell and deliver it to its destination. In neurons, that can release copper into the synaptic cleft, chaperones introduce copper ions to the ATP7A protein, which transport it to the lumen of a vesicle. After Cu release, it can interact with e.g., NMDAR.

Figure 5

Hepcidin expression via bone morphogenic protein (BMP)-SMAD signaling pathway in hepatocytes. High iron concentration in plasma increases transferrin saturation, which results in homeostatic iron regulator protein (HFE) detachment from the transferrin receptor (TFRC)/HFE complex, then its interaction with ALK3 (BMP receptor), which leads to increased expression of ALK3 and activation of the BMP-SMAD signaling pathway. High plasma iron also causes stabilization of TFR2, which is associated with HFE, and may also interact with ALK3 (but this is not confirmed). Hemojuvelin (HJV) is a co-receptor for BMP, and TMPRSS6 protein cleaves HJV acting as an inhibitor of HJV expression.