Fig. 1.

Calcium homeostasis in the physiological state and Parkinson’s disease Under physiological conditions, Ca²⁺ shuttles between the extracellular space, cytoplasm, endoplasmic reticulum (ER), mitochondria, lysosomes, and Golgi bodies, and maintains a stable amplitude and frequency of Ca²⁺ changes in different cellular compartments, which are strictly regulated by many types of Ca²⁺ channels or Ca²⁺ pumps. In the Parkinson’s disease state, aggregated α-synuclein, mutant PD-related genes (such as LRRK2, DJ-1, Parkin, and PINK), alter the levels of Ca²⁺ channels or damaged the cell membrane, causing imbalanced Ca²⁺ signaling between different cellular compartments, and thereby contribute to nigral dopaminergic neuron death. VGCC, voltage-gated Ca²⁺ channel; ROC, receptor-operated channel; TRP, transient receptor potential channel; ORAI, Ca²⁺ release-activated Ca²⁺ channel modulator; NCX, Na⁺/Ca²⁺ exchanger; PMCA, Ca²⁺ ATPase; ER, endoplasmic reticulum; SERCA, sarco-endoplasmic reticulum Ca²⁺-ATPase; RYR, ryanodine receptor; STIM, stromal interaction molecule; IP3, inositol-1, 4, 5-triphosphate; VDAC, voltage-dependent anion channel; MAM, mitochondria-associated endoplasmic reticulum membrane; MCU, mitochondrial Ca²⁺ uniporter; MICU1/2, mitochondrial Ca²⁺ uptake 1/2; OXPHOS, oxidative phosphorylation; TRC2/3, two-pore channels 2/3; P2X4, ATP-gated multi-ion channel; TRPML1, mucolipin-1; LRRK2, leucine-rich repetitive kinase 2; ROS, reactive oxygen species.