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

Abstract

The Na⁺/Ca²⁺ exchanger (NCX) protein family is a part of the cation/Ca²⁺ exchanger superfamily and participates in the regulation of cellular Ca²⁺ homeostasis. NCX1, the most important subtype in the NCX family, is expressed widely in various organs and tissues in mammals and plays an especially important role in the physiological and pathological processes of nerves and the cardiovascular system. In the past few years, the function of NCX1 in the digestive system has received increasing attention; NCX1 not only participates in the healing process of gastric ulcer and gastric mucosal injury but also mediates the development of digestive cancer, acute pancreatitis, and intestinal absorption. This review aims to explore the roles of NCX1 in digestive system physiology and pathophysiology in order to guide clinical treatments.

Keywords: Calcium; Digestive system diseases; Ion channel; Na+/Ca2+ exchanger; Sodium.

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.