FIG. 1.

Schematic representation of key regulators of cytosolic Ca²⁺. Ca²⁺ enters cytosol from the extracellular milieu through channels situated on the plasma membrane, such as LGCCs that are permeable to Ca²⁺ (such as purinergic receptors, CNG channels, AChRs, AMPARs, NMDARs, KARs), mechanosensitive Piezo1 and Piezo2 channels, VGCCs, TRP channels, and ORAI (the plasma membrane part of CRAC). ORAI is activated by STIM upon ER/SR Ca²⁺ depletion. Ca²⁺ efflux can occur through PMCA or NCX. Intercellular Ca²⁺ exchange can occur through gap junction channels. ER/SR Ca²⁺ release through RYR can be activated by cytosolic Ca²⁺ elevation or VGCC conformation change. IP₃R Ca²⁺ release can be initiated by cytosolic Ca²⁺ elevation or IP₃ produced by PLC upon the activation of G-protein-coupled receptors. Ca²⁺ influx into ER/SR can be mediated by SERCA. Mitochondrial Ca²⁺ intake mainly occur through MCU, while the efflux can occur through NCLX or mPTP formed by dimers of ATP synthase. For nuclear Ca²⁺ signaling, a representative example is the dephosphorylation of NFAT by calcineurin and its nuclear translocation. Calcineurin is activated by calmodulin upon Ca²⁺ binding. AChR, acetylcholine receptor; AMPAR, AMPA receptor; CNG, cyclic nucleotide-gated; CRAC, Ca²⁺ release-activated channel; ER/SR, endoplasmic reticulum/sarcoplasmic reticulum; KAR, kainate receptor; LGCCs, ligand-gated cation channel; MCU, mitochondrial Ca²⁺ uniporter; mPTP, mitochondrial permeability transition pore; NCLX, Na⁺/Ca²⁺/Li⁺ exchanger; NCX, Na⁺/Ca²⁺ exchanger; NMDAR, N-methyl-D-aspartate receptor; ORAI, Ca²⁺ release-activated Ca²⁺ channel protein; PLC, phospholipase C; PMCA, plasma membrane Ca²⁺ ATPase; RYR, ryanodine receptor; SERCA, sarcoendoplasmic reticulum Ca²⁺ pump; STIM, stromal interaction molecule; TRP, transient receptor potential; VGCC, voltage-gated Ca²⁺ channel.