Fig. 1: Intracellular Ca²⁺ trafficking.

Ca²⁺ ions are constantly transferred from the cytoplasm to the extracellular space, through the action of the plasma membrane Ca²⁺ ATPase PMCA and Na⁺/Ca²⁺ (NCX) or Na⁺/Ca²⁺-K⁺ (NCKXs) exchangers. Opening of voltage-gated or ligand-gated plasma membrane Ca²⁺ channels (VGCCs or LGCCs) results in the rapid influx of Ca²⁺ ions along their chemical gradient. Inside the cell, large amounts of Ca²⁺ are transferred in the ER by the sarcoendoplasmic reticulum Ca²⁺-ATPase (SERCA) and can be released upon stimulation via IP₃R or RyR channels. Depletion of ER Ca²⁺ stores induces the translocation of STIM protein to ER/PM contact sites where it activates the Ca²⁺ channel Orai to mediate prolonged influx of extracellular Ca²⁺. Ca²⁺ is also stored in the cis-Golgi through its transfer by SERCA or the trans-Golgi via the Ca²⁺-ATPase SPCA and can be released through IP₃R or RyR channels, respectively. The Ca²⁺ content of lysosomes, built up by the transfer of ions from the cytoplasm via an unidentified importer, can be released through the action of transient receptor potential mucolipin channels (TRPML) and two-pore channels (TPC). The OMM is easily penetrated by Ca²⁺ ions that pass through VDAC but has to be transferred by the highly selective mitochondrial Ca²⁺ uniporter (mtCU) complex of the IMM in order to reach the matrix. Ca²⁺ export from mitochondria is mediated by the Na⁺/Ca²⁺ exchanger NCLX and the Ca²⁺/H⁺ antiporter Leucine Zipper And EF-Hand Containing Transmembrane Protein 1 (LETM1). Ca²⁺ overload or dissipation of Δψ_m can induce the opening of the mitochondrial permeability transition pore (mPTP), which mediates the rapid efflux of Ca²⁺ to the cytoplasm. Depolarization (shown in red) or altered pH (shown in yellow) can allow the reversal of NCLX or LETM1, respectively, transforming them into Ca²⁺ importers that function with different properties than the mtCU. For details see text. Created in BioRender. Palikaras, K. (2024) https://BioRender.com/v71t847.