Roles of Na+/Ca2+ exchanger 1 in digestive system physiology and pathophysiology

Figure 1 Structural features of NCX1.

Figure 2 The regulated signal pathways and transcription factors of NCX1 in digestive diseases. Transforming growth factor-β (TGF-β) stimulates the activation of PLC-IP3 and Ca²⁺ release from the endoplasmic reticulum, which activates TRPC1 and the reverse mode of NCX1 resulting in Ca²⁺ influx, and the increase of Ca²⁺ mediates cell motility directly or indirectly via activation of Ca²⁺-dependent PKC in pancreatic cancer. Cerulein activates NCX1 and induces activation of inflammatory factors TNF-α and IL-6 and the downstream NK-κB pathway in pancreatic cells. TGF-β can upregulate the expression of NCX1 and TRPC6 and activate the downstream SMAD pathway to regulate the migration and invasion of hepatocellular carcinoma cells.

Figure 3 The effects of NCX1 positive mode in the digestive system. Under normal circumstances, NCX1 adopts the positive mode in esophageal smooth muscle and gastric smooth muscle, excreting Ca²⁺ from the cells, reducing intracalcium concentration and inducing smooth muscle relaxation. In the jejunum, vitamin D and 1,25-(OH)₂D₃ can enhance the expression and activity of NCX1 to increase the excretion of Ca²⁺. NCX1 mainly adopts the forward control mode in ischemic-reperfusion injury. Trisulfated disaccharide (TD) can transport excess intracellular Ca²⁺ out of the cell by activating NCX1.

Figure 4 The roles of NCX1 reverse mode in the digestive system. In duodenal epithelial cells, carbachol and 5-HT can activate the reverse mode of NCX1, enhancing Ca²⁺ influx to release HCO₃^-. In hepatoma cells, NHE1 can promote H⁺ excretion and Na⁺ influx and activate the reverse mode of NCX1 to induce Ca²⁺ influx. In colon goblet cells, ATP activates the TRPM5 channel to induce Na⁺ influx, and an increase of Na⁺ concentration starts the NCX1 reverse mode and increases Ca²⁺ influx and MUC5AC expression. In pancreatic islet β cells, under glucose stimulation, NCX1 can be converted to a reverse mode to promote Ca²⁺ influx to increase insulin secretion.