| Symbol: | TRPM2 |
| UniProt: | O94759 |
| Gene: | TRPM2 |
| Molecular Weight: | 171 kDa |
| Location: | Plasma membrane, lysosomal membrane |
| PDB: | 6PUS, 6PUJ |
TRPM2 (Transient Receptor Potential Melastatin 2) is a calcium-permeable cation channel activated by oxidative stress and ADP-ribose. It serves as a sensor linking cellular oxidative damage to calcium influx, making it a key mediator of neuronal death in Alzheimer's disease, Parkinson's disease, and ischemic stroke. TRPM2 activation creates a feed-forward loop of calcium overload and oxidative damage that drives neurodegeneration.[1][2]
TRPM2 is a large tetrameric channel with distinct functional regions:
The cryo-EM structure reveals a unique "molecular sensor" architecture where ADP-ribose binding at the NUDT9-H domain triggers pore opening.[3]
TRPM2 is activated by products of oxidative damage:[4]
Under normal conditions, TRPM2 functions in:
TRPM2 amplifies calcium signals through:[5]
TRPM2 contributes to Aβ toxicity:[6]
Oxidative stress in dopaminergic neurons involves TRPM2:[7]
TRPM2 is a major mediator of ischemic damage:[8]
Motor neuron vulnerability involves TRPM2:[9]
Several compounds show TRPM2 inhibition:[10]
Perraud AL et al. ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature. 2001. ↩︎
Hara Y et al. LTRPC2 Ca²⁺-permeable channel activated by changes in redox status confers susceptibility to cell death. Molecular Cell. 2002. ↩︎
Wang L et al. Structure and gating mechanism of the transient receptor potential channel TRPM2. Science Signaling. 2018. ↩︎
Sumoza-Toledo A, Penner R. TRPM2: a multifunctional ion channel for calcium signalling. Journal of Physiology. 2011. ↩︎
Du J et al. Calcium-sensing mechanism in TRPM2 channel. Journal of Biological Chemistry. 2009. ↩︎
Ostapchenko VG et al. The TRPM2 channel is required for neuronal viability and protects against amyloid β toxicity. Cell Death & Differentiation. 2015. ↩︎
Ye M et al. TRPM2 channel deficiency prevents delayed neuronal death in the hippocampus after brain ischemia. Cell Death & Disease. 2014. ↩︎
Shimizu S et al. Cyclin-dependent kinase 5 and calcium/calmodulin-dependent kinase II mediate the phosphorylation of TRPM2 at Ser-39 that promotes cell death. Journal of Biological Chemistry. 2016. ↩︎
Hermosura MC et al. Altered functional expression of TRPM2 channels in familial ALS fibroblasts. Cell Calcium. 2019. ↩︎
Kashio M et al. Redox signal-mediated sensitization of transient receptor potential melastatin 2 (TRPM2) to temperature affects macrophage functions. Proceedings of the National Academy of Sciences USA. 2012. ↩︎