Novel role of TRPM4 ion channel in exocytosis

Under physiological conditions, the widely expressed calcium-activated TRPM4 channel conducts sodium into the cell. This sodium influx depolarizes the plasma membrane and reduces the driving force for calcium entry. Aberrant expression or function of TRPM4 has been reported in various diseases, including different types of cancer. TRPM4 is localized mainly in the plasma membrane, but is also found in intracellular vesicles, which can undergo exocytosis. In this study, we show that calcium-induced exocytosis in the colorectal cancer cell line HCT116 is dependent on TRPM4. In addition, findings from prostate cancer cell lines point to a more general role for TRPM4 in calcium-induced exocytosis in cancer cells. Furthermore, calcium-induced exocytosis depends on TRPM4 ion conductivity. Additionally, an increase in intracellular calcium results in the delivery of TRPM4 to the plasma membrane. This process also depends on TRPM4 ion conductivity. TRPM4-dependent exocytosis and delivery of TRPM4 to the plasma membrane is mediated by SNARE proteins. Finally, we provide evidence that calcium-induced exocytosis depends on TRPM4 ion conductivity not within the plasma membrane, but rather in TRPM4-containing vesicles.