Figure 2. TRPM2 Maintains Cell Survival through Modulation of HIF-1/2α, CREB, Nrf2, and Pyk2.

TRPM2 mediates expression of HIF-1/2α, CREB, and Nrf2 in neuroblastoma cells. Pyk2 phosphorylation and activation by TRPM2 through a Ca²⁺-dependent process is involved in modulating CREB expression. These factors contribute to maintenance of mitochondrial function and ATP production, and lower ROS levels through reduced ROS production and preservation of the antioxidant response. When TRPM2 is inhibited or depleted, Ca²⁺ influx into the cell and into mitochondria through the mitochondrial calcium uniporter (MCU) is reduced, expression of key transcription factors HIF-1/2α, CREB, and Nrf2 is decreased, mitochondrial function, cellular bioenergetics, and autophagy/mitophagy are impaired, activation of kinases including Pyk2 and Src and cell viability are reduced, and ROS levels and sensitivity to chemotherapy are increased.