Calcium Signaling Pathway

All physiological activities are regulated by Ca²⁺, and the basis of Ca²⁺ as a cellular messenger is the presence of a concentration gradient between cytosolic Ca²⁺ and intracellular stores or extracellular Ca²⁺. Ca²⁺ signaling is very flexible and at the same time tightly controlled. Ca²⁺ plays an important role in the regulation of cellular functions, such as nerve conduction, muscle contraction, morphological changes, nerve cell aging, secretion of gland cells and signal transmission of retinal cells. Many cellular functions depend on the extremely high difference between the intracellular and extracellular Ca²⁺ concentration. Once the difference between the intracellular and extracellular Ca²⁺ concentration is reduced, cellular functions will be damaged, and even cell death will be caused. Cytosolic Ca²⁺ comes from two sources: One is the extrinsic calcium entry pathway. Calcium channels are a class of transmembrane glycoproteins that form hydrophilic pores that approximate a funnel. They can be divided into three main categories: voltage-gated calcium channels (VOC), receptor-gated calcium channels (ROC), and store-controlled calcium channels (SOC). Among them, voltage-gated calcium channels catalyze rapid, highly selective Ca²⁺ influx into cells. The other major source is internal storage, which is mainly located in the endoplasmic reticulum/sarcoplasmic reticulum (ER/SR). There are two intracellular calcium release channels, IP3 and RYR receptor channels, which release calcium ions from ER/SR calcium stores. The main activator of these channels is Ca²⁺ itself, and this process of Ca²⁺ induced Ca²⁺ release is central to the Ca²⁺ signaling mechanism. Various second messengers or regulators also control Ca²⁺ release. IP3 regulates IP3R through the phospholipase C pathway. Cyclic ADP-ribose (cADPR) releases Ca²⁺ through RYRs. Nicotinic acid adenine dinucleotide phosphate (NAADP) stimulates Ca²⁺ release from acidic stores such as lysosomes and is a highly potent second messenger for calcium mobilization. Ca²⁺ released through the NAADP-sensitive mechanism may also feed back to RYR or IP3R. cADPR and NAADP are generated by CD38. The enzyme may be sensitive to cellular metabolism because ATP and NADH inhibit it. In addition, mitochondrial Ca²⁺ uptake is critical for cell survival and death. A calcium uniporter located in the inner mitochondrial membrane, responsible for mediating calcium uptake. This complex consists of two components, the selective calcium channel MCU and its regulator MICU1.