Figure 2.

Simplified scheme of Ca²⁺ dynamics inside the cell and its relation to ER stress. In excitable cells such as neurons, Ca²⁺ ions enter the cell through ligand-gated and voltage-gated channels (1—pink circle). The Ca²⁺ gradient across the cell membrane is actively maintained by the PMCA pump (2—pink circle). The ER is the main Ca²⁺-storing organelle. Ca²⁺ is transported against a steep concentration gradient into the lumen of the ER via the SERCA pump (3—pink circle). Upon ligand stimulation, Ca²⁺ ions are released from the reticulum into the cytosol via the IP3Rs and RyRs to activate Ca²⁺-dependent proteins and mediate stimulus-response signaling. The refilling of intracellular Ca²⁺ stores by extracellular Ca²⁺ occurs via SOCE (4—pink circle) by close apposition of the transmembrane proteins STIM1 and ORAI. Filamin A, an actin-binding protein, interacts with PERK independently from the UPR. This interaction seems to be crucial for the formation of juxtapositions of the ER membrane with the plasma membrane, the proximity of the two membranes being a precondition for SOCE to occur. Protein translocation across the ER membrane is mediated via the Sec61 translocon (1—light blue circle). At the end of the translocation process, the Sec61 channel mediates the efflux of Ca²⁺ from the ER to the cytosol resulting in a reduction in [Ca²⁺]_ER (2—light blue circle). The ER chaperone BiP binds to the translocon to close it and block the Ca²⁺ efflux from the ER (3-light blue circle). Efficient Ca²⁺ flux from the ER to mitochondria is mediated via IP3Rs, the voltage-dependent anion channel 1 (VDAC1), which is located at the outer mitochondrial membrane, and mitochondrial Ca²⁺ uniporter 1 (MCU1), located at the inner mitochondrial membrane. The IP3Rs–VDAC1 interaction is facilitated by the chaperone GRP75, which is enriched in MAMs. Created with biorender.com (www.biorender.com, accessed on 27 November 2022).