{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTRPM2 is a widely expressed, Ca²⁺‐permeable nonselective cation channel that acts as a versatile sensor of the intracellular redox state. It is directly activated by adenosine diphosphate ribose (ADPR) and is modulated by secondary messengers – including cyclic ADPR, nicotinate adenine dinucleotide phosphate, and, in some models, oxygen-derived species such as hydrogen peroxide – to induce Ca²⁺ and Na⁺ influx. These activation events depend on intrinsic channel features such as a C‐terminal NUDT9‐homology domain, critical ligand‐binding pockets, and an IQ-like motif that recruits calmodulin, as well as on structural determinants such as coiled–coil–mediated oligomerization revealed by cryo–electron microscopy. Collectively, these studies show that channel gating by ADPR (often produced via PARP activation) is highly dependent on the intracellular Ca²⁺ level and redox environment, with additional modulation by temperature and sirtuin–dependent metabolites."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its core biophysical properties, TRPM2 plays a pivotal role in numerous cellular and pathological processes. In immune cells such as lymphocytes, monocytes, and neutrophils, TRPM2–mediated Ca²⁺ influx is critical for responses to oxidative stress, for regulating cytokine production, for modulating phagocyte activity, and for triggering apoptosis upon exposure to pro–oxidant or inflammatory stimuli. Aberrant TRPM2 activation has been implicated in neuronal toxicity through amyloid–induced and dopaminergic cell death, in predisposition to neurodegenerative diseases via channel variants, and in cancer–related functions – where differential expression of full–length and short (dominant negative) isoforms modulates proliferation, bioenergetics, and chemosensitivity. Other studies have linked TRPM2 function to endothelial permeability, autophagy suppression, and genetic associations with psychiatric illnesses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "46"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTRPM2 activity also contributes to tissue–selective responses in diverse physiological and pathological contexts. In the heart, proper TRPM2–mediated Ca²⁺ entry preserves mitochondrial function and limits oxidative injury. In pancreatic β–cells, TRPM2 activation is linked to insulin secretion and cell death in diabetes models; meanwhile, in irradiated exocrine glands, aberrant TRPM2 activation underlies persistent gland dysfunction. These findings, alongside evidence connecting TRPM2 channel behavior to enhanced bactericidal capacity of neutrophils, underscore the channel’s potential as a therapeutic target in conditions ranging from ischemia–reperfusion injury to cancer and neurodegeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "47"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yuji Hara, Minoru Wakamori, Masakazu Ishii, et al. 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