TRPM2: bridging calcium and ROS signaling pathways-implications for human diseases

Abstract

TRPM2 is a versatile and essential signaling molecule that plays diverse roles in Ca²⁺ homeostasis and oxidative stress signaling, with implications in various diseases. Research evidence has shown that TRPM2 is a promising therapeutic target. However, the decision of whether to activate or inhibit TRPM2 function depends on the context and specific disease. A deeper understanding of the molecular mechanisms governing TRPM2 activation and regulation could pave the way for the development of innovative therapeutics targeting TRPM2 to treat a broad range of diseases. In this review, we examine the structural and biophysical details of TRPM2, its involvement in neurological and cardiovascular diseases, and its role in inflammation and immune system function. In addition, we provide a comprehensive overview of the current knowledge of TRPM2 signaling pathways in cancer, including its functions in bioenergetics, oxidant defense, autophagy, and response to anticancer drugs.

Keywords: TRPM2 cation channels; autophagy; bioenergetics; calcium signal; oxidant defense; oxidative stress.

FIGURE 1

Schematic representation of the main structure of the TRPM2 channel and the gating mechanism—Modified from (Wang et al., 2018) (A) TRPM2 major domain sizes, with residue numbers indicating the start and end of each domain. (B) TRPM2 special organization showing 1) the transmembrane domain composed of six transmembrane segments (TMS) with a pore between fifth and sixth TMS; 2) a cytoplasmic TRPM2 N-terminal containing four homology regions (MHR1-4); 3) a cytoplasmic TRPM2 C-terminal displaying the NUDT9H domain, where ADPR initiate TRPM2 activation. (C) A diagram representing TRPM2 gating. [a] In the absence of ADPR and Ca²⁺, transmembrane segment 6 (S6) (yellow) closes the channel gate of TRPM2 (top left). In this condition, the pore of the TRPM2 homotetramer is closed (lower left). [b] Upon ADPR binding, NUDT9H (grey) undergoes conformational changes that trigger rotation of MHR1/2 (thin purple), exposing the channel vestibule (top middle). In this condition, the pore of TRPM2 homotetramer is closed (bottom center). [c] ADPR-mediated conformational changes allow Ca²⁺ binding to TMS3 (orange) and TRP H1 (cyan), causing TRP H1 to tilt and pull S6, resulting in rotation of S6 and channel opening (top right). In this state, the pore of the TRPM2 homoteramer is open (bottom right).

FIGURE 2

TRPM2 is essential in cancer survival and progression through the control of the fueling and oxidant-defense systems—Inspired from (Chen et al., 2020). Elevated ROS induces TRPM2-mediated Ca²⁺ to (1) directly coupled to mitochondrial Ca²⁺ uptake (mCU) to supply ATP production, thereby fueling program, and (2) trigger oxidant-defense by activating NRF2 phosphorylation, allowing its transfer and accumulation into the nucleus, which leads to the induction of a wide array of antioxidant genes. Simultaneously, TRPM2-mediated Ca²⁺ influx activates autophagy/mitophagy through the activation of CREB, ATF4, and ULK, thereby promoting mitophagy and maintenance of mitochondrial quality. On one hand, elevated ROS production guarantees increasing TRPM2 activity and thus increased ATP production, using a positive-feedback mechanism (1– ROS-On system); on the other hand, ROS-scavenging proteins and mitophagy buffer ROS from reaching levels that incur cell-damage (2—ROS-OFF system).