TRPM7 and TRPM8 Ion Channels in Pancreatic Adenocarcinoma: Potential Roles as Cancer Biomarkers and Targets

Figure 2

A working model for the signaling mechanisms that mediate the cellular functions of TRPM7 in pancreatic adenocarcinoma. Low intracellular level of Mg²⁺ or phosphatidylinositol-4,5-bis-phosphate (PIP₂) activates the ion channel of TRPM7. Once activated, TRPM7 allows inflow of Mg²⁺ and/or Ca²⁺ from the extracellular medium into the cytosol. The rise of intracellular Mg²⁺ leads to activation of intracellular reactions that result in cellular proliferation, survival, and migration. On the other hand, the Ca²⁺ influx leads to activation of Ca²⁺-sensitive phospholipase C (PLC) and hydrolysis of PIP₂, thus providing negative feedback inhibition of TRPM7 activity. Hydrolysis of PIP₂ produces inositol-1,4,5-triphosphate (IP₃), which triggers intracellular Ca²⁺ release and produces diacylglycerol (DAG). The increased Ca²⁺ or DAG activates protein kinase C (PKC). PKC in turn activates RAF in the RAS/ERK pathway, leading to transcription of a variety of genes and resulting in cellular proliferation, survival, and migration.