Intracellular Calcium Signaling: From Second Messenger to Targeted Therapy

Calcium is an essential element for cellular life activities. Cells generate calcium signals through the precise regulation of Ca²⁺ influx and efflux. As a key second messenger, calcium regulates diverse cellular processes including cell proliferation, metabolism, migration, immunity, cell death, neurotransmitter transmission and synaptic communication. The increase in intracellular Ca²⁺ concentration is precisely controlled by two mechanisms: the influx of extracellular Ca²⁺ and the release from intracellular dynamic calcium stores. Both processes rely on molecular machinery with specific subcellular localization and functional roles, essential for maintaining calcium homeostasis.

Calcium channels serve as the primary pathway for increasing intracellular Ca²⁺ levels. These transmembrane proteins mediate controlled Ca²⁺ entry from the extracellular space into the cytoplasm. Their selective permeability and gating mechanisms are fundamental for the precise regulation of calcium homeostasis. For example, VGCCs, predominantly expressed in excitable cells such as neurons and muscle cells, are involved in action potential propagation and muscle contraction. They are activated by changes in membrane potential, and subsequent NMDAR-mediated sustained hyperpolarization further increases intracellular calcium concentration. ROCs are activated by extracellular signaling molecules (e.g., neurotransmitters and hormones) and participate in intercellular communication. Their activation typically involves GPCR-mediated stimulation of PLC, leading to the production of IP₃. IP₃ then binds to its receptors on the endoplasmic reticulum, promoting calcium release from stores and further activating ROCs. SOCs, including the CRAC formed by STIM1 and Orai1 interaction, are widely expressed in immune cells and tumor cells. The endoplasmic reticulum, mitochondria, and sarcoplasmic reticulum represent the three major intracellular calcium stores. Cells employ multiple calcium-buffering mechanisms to ensure dynamic equilibrium of cytosolic calcium levels. For instance, the endoplasmic reticulum actively accumulates Ca²⁺ via the SERCA pump. Upon cell stimulation, stored Ca²⁺ is released through channels such as IP₃ receptors (IP₃Rs) and RyRs, thereby elevating intracellular calcium concentration. Additionally, other cellular calcium transporters, including PMCA, SERCA, and NCX, play crucial roles in maintaining intracellular calcium homeostasis by extruding Ca²⁺ from the cell or sequestering it into intracellular stores^[2].

Dysregulation of calcium homeostasis leads to disrupted calcium signaling and can contribute to the pathogenesis of various major diseases. In Alzheimer's disease (AD), disrupted intracellular calcium homeostasis is associated with Amyloid-β (Aβ) deposition, Tau hyperphosphorylation, synaptic plasticity abnormalities, and apoptosis. The mPTP helps maintain mitochondrial calcium homeostasis, and inhibition of mPTP has been shown to improve cognitive deficits in AD transgenic mice. MICU1, an endogenous endothelial protective factor, helps prevent vascular inflammation and atherosclerosis by maintaining mitochondrial Ca²⁺ homeostasis. Calcium signaling pathways regulate cytoskeletal dynamics, intercellular communication, and MMP secretion, thereby influencing the migration and invasion of tumor cells. Furthermore, it also modulates interactions between tumor cells (including endothelial and immune cells) and their tumor microenvironment, which is critical for angiogenesis and immune escape^[1][3][4].