TRPM2 channel-mediated cell death: An important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions

Abstract

Oxidative stress resulting from the accumulation of high levels of reactive oxygen species is a salient feature of, and a well-recognised pathological factor for, diverse pathologies. One common mechanism for oxidative stress damage is via the disruption of intracellular ion homeostasis to induce cell death. TRPM2 is a non-selective Ca²⁺-permeable cation channel with a wide distribution throughout the body and is highly sensitive to activation by oxidative stress. Recent studies have collected abundant evidence to show its important role in mediating cell death induced by miscellaneous oxidative stress-inducing pathological factors, both endogenous and exogenous, including ischemia/reperfusion and the neurotoxicants amyloid-β peptides and MPTP/MPP⁺ that cause neuronal demise in the brain, myocardial ischemia/reperfusion, proinflammatory mediators that disrupt endothelial function, diabetogenic agent streptozotocin and diabetes risk factor free fatty acids that induce loss of pancreatic β-cells, bile acids that damage pancreatic acinar cells, renal ischemia/reperfusion and albuminuria that are detrimental to kidney cells, acetaminophen that triggers hepatocyte death, and nanoparticles that injure pericytes. Studies have also shed light on the signalling mechanisms by which these pathological factors activate the TRPM2 channel to alter intracellular ion homeostasis leading to aberrant initiation of various cell death pathways. TRPM2-mediated cell death thus emerges as an important mechanism in the pathogenesis of conditions including ischemic stroke, neurodegenerative diseases, cardiovascular diseases, diabetes, pancreatitis, chronic kidney disease, liver damage and neurovascular injury. These findings raise the exciting perspective of targeting the TRPM2 channel as a novel therapeutic strategy to treat such oxidative stress-associated diseases.

Keywords: Ca(2+) and Zn(2+) homeostasis; Cell death; Diseases; Oxidative stress; TRPM2 channel.

Graphical abstract

Fig. 1

The molecular and activation properties of the TRPM2 channel. (A) A cartoon representation of the tetrameric TRPM2 channel and its subunit, which is comprised of 6 transmembrane domains (S1–S6) with a re-entrant loop between S5 and S6 that forms a pore permeable to Ca²⁺, K⁺ and Na⁺. The intracellular N-terminus contains four MHR (1–4), and the intracellular C-terminus contains aCC tetramerization domain and a NUDT9-H domain. The TRPM2 channel is activated by binding of intracellular ADPR at two sites, the MHR1/2 and NUDT9-H domain, and Ca²⁺ binding to the intracellular face of the transmembrane domain (not depicted). (B) ADPR and structurally related compounds that activate the TRPM2 channel, with the reported EC₅₀ value shown in brackets where available. (C) Activation of the TRPM2 channel by ROS. Accumulation of intracellular ROS, resulting from exposure to extracellular ROS, increased intracellular ROS generation or decreased antioxidant capacity, induces activation of PARP and PARG enzymes in the nucleus that convert NAD⁺ to ADPR. ADPR diffuses into the cytosol and opens the TRPM2 channel, permitting Ca²⁺ influx to increase intracellular Ca²⁺ concentration, or activates the TRPM2 channel in intracellular organelles (not depicted). Abbreviations: ADPR, ADP-ribose; CC, coiled-coil; EC₅₀, the concentration evoking 50% of the maximal response; MHR: TRPM homology regions; NAD⁺, nicotinamide adenine dinucleotide; NUDT9-H: NUDT9 homology; PARG, poly(ADPR) glycohydrolase; PARP, poly(ADPR) polymerase; ROS, reactive oxygen species.

Fig. 2

TRPM2-mediated signalling pathways in oxidative stress-induced neuronal death associated with ischemia/reperfusion brain damage, AD and PD. (A) Delayed neuronal cell death associated with ischemia/reperfusion brain damage. OS resulting from reperfusion, based on examining H₂O₂-induced delayed neuronal cell death in human neuroblastoma SH-SY5Y cells, stimulates activation of PKC and NOX, and NOX-mediated ROS production. ROS induces activation of PARP and the TRPM2 channel, and TRPM2-mediated Ca²⁺ influx. ROS also induces lysosomal dysfunction and lysosomal Zn²⁺ release. TRPM2-dependent mitochondrial Zn²⁺ accumulation leads to mitochondrial dysfunction and cell death. The cell death mechanisms or pathways are unclear. Mitochondrial dysfunction also leads to ROS generation. (B) Aβ42-induced cell death in hippocampal neurons associated with AD. Exposure to Aβ42 at pathologically relevant concentrations induces a similar signalling pathway as described in (A) to cause mitochondrial dysfunction and release of cytochrome c. (C) MPP⁺-induced neuronal cell death related to PD, based on examining MPP⁺-induced cell death in SH-SY5Y cells. Exposure to MPP⁺ promotes ROS generation that activates the TRPM2 channel, likely via PARP, leading to intracellular Ca²⁺ increase, activation of calpain and pro-apoptotic proteins (Bak, Bid and Bad), cyt c release, and caspase-3 activation to initiate apoptotic cell death. Abbreviations: Aβ, amyloid-β peptide; ADPR, ADP-ribose; AD, Alzheimer's disease; cyt c, cytochrome c; MPP⁺, 1-methyl-4-phenylpyridinium; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NOX, NADPH oxidase; PARP, poly(ADPR) polymerase; PD, Parkinson's disease; PKC, protein kinase C; ROS, reactive oxygen species.

Fig. 3

TRPM2-mediated signalling pathways in oxidative stress-induced pericyte death associated with neurovascular injury induced by exposure to nanoparticles. Exposure to ZnO-NPs increases ROS generation to induce TRPM2 channel activation, possibly via PARP and also generation of peroxynitrite for TRPM2 nitration to upregulate the channel activity in pericytes. TRPM2 channel activation leads to intracellular Ca²⁺ increase and ER stress that induces autophagy and caspase-8 activation to cause pericyte death by apoptosis. Abbreviations: ADPR, ADP-ribose; ER, endoplasmic reticulum; PARP, poly(ADPR) polymerase; ROS, reactive oxygen species; ZnO-NPs, zinc oxide nanoparticles.

Fig. 4

TRPM2-mediated signalling pathways in oxidative stress-induced cardiomyocyte death associated with myocardial ischemia/reperfusion injury. (A) H₂O₂-induced neonatal cardiomyocyte death. Exposure to H₂O₂ induces apoptotic cell death via activation of PARP and the TRPM2 channel, TRPM2-mediated Na⁺ and Ca²⁺ influx and subsequent MCU-mediated mitochondrial Na⁺ and Ca²⁺ overloading, leading to mitochondrial dysfunction, cyt c release and caspase-3 activation to initiate apoptotic cell death. Exposure to H₂O₂ also induces necrotic cell death as a result of PARP-dependent and TRPM2-indpendent depletion of ATP. (B) TNF-α-induced adult cardiomyocyte death. Exposure to TNF-α induces caspase-8-dependent mitochondrial ROS generation, activation of PARP and the TRPM2 channel, TRPM2-mediated Ca²⁺ influx and cell death via unknown mechanism(s). (C) TRPM2 channel activation in adult cardiomyocytes has been proposed to play an opposing role by protecting against cardiomyocyte death induced by H₂O₂ or myocardial I/R. TRPM2-mediated Ca²⁺ influx activates Ca²⁺-dependent PYK2 kinase and ERK1/2 and Akt, downstream pro-survival signalling. PYK2 is also translocated to mitochondria and upregulates MCU function and MCU-mediated Ca²⁺ into mitochondria to maintain mitochondrial function and reduce mitochondrial ROS generation. Abbreviations: ADPR, ADP-ribose; cyt c, cytochrome c; ERK, extracellular signal-regulated kinase; MCU, mitochondrial Ca²⁺ uniporter; PARP, poly(ADPR) polymerase; PYK2, proline-rich tyrosine kinase 2; ROS, reactive oxygen species; TNF-α, tumour necrosis factor-α.

Fig. 5

TRPM2-mediated signalling pathways in oxidative stress-induced endothelial cell death associated with endothelial barrier dysfunction and vascular diseases. Two distinctive but overlapping signalling mechanisms mediate H₂O₂-induced endothelial death. (A) Exposure to H₂O₂ induces apoptotic cell death via activation of PARP and the TRPM2 channel, TRPM2-mediated Ca²⁺ influx and subsequent activation of caspase-3, caspase-8 and caspase-9 activation to initiate apoptotic cell death. Exposure to TNF-α also induces apoptotic cell death through the same signalling mechanism. (B) Exposure to H₂O₂ also induces PKCα activation, which in turn phosphorylates TRPM2-S and promotes dissociation of TRPM2-S with, and releases its inhibition of, the TRPM2 channel, resulting in increased TRPM2-mediated Ca²⁺ influx and caspase-3 activation. ROS generation by GO in the presence of glucose induces endothelial cell death via the signalling mechanisms presented in (B). Abbreviations: ADPR, ADP-ribose; GO, glucose oxidase; PARP, poly(ADPR) polymerase; PKCα, protein kinase Cα; ROS, reactive oxygen species; TNF-α, tumour necrosis factor-α.

Fig. 6

TRPM2-mediated signalling pathways in oxidative stress-induced pancreatic cell death associated with diabetes and acute biliary pancreatitis. (A) STZ-induced cell death in pancreatic β-cells associated with type 1 diabetes. Exposure to STZ induces an increase in the ROS level and PARP-dependent TRPM2 channel activation, leading to cell death in a signalling pathway elucidated mainly based on examining H₂O₂-induced cell death in INS-1 insulin-secreting cells. Activation of the TRPM2 channel on the cell surface induces Ca²⁺ influx and intracellular Ca²⁺ increase, and activation of TRPM2 in the lysosomes results in lysosomal Zn²⁺ release. Alterations in intracellular Ca²⁺ and Zn²⁺ homeostasis lead to apoptosis. (B) Palmitate-induced cell death in pancreatic β-cells associated with type 2 diabetes. Exposure to palmitate triggers activation of NOX for ROS generation. ROS-induced PARP-dependent TRPM2 channel activation in the lysosomes results in lysosomal Zn²⁺ release, mitochondrial Zn²⁺ accumulation, recruitment of Drp1 to mitochondrial and Drp1-mediated mitochondrial fission, leading to mitochondrial dysfunction and apoptosis. (C) Bile acid-induced cell death in pancreatic acinar cells associated with acute biliary pancreatitis. Exposure to CDC induces ROS generation and TRPM2 channel activation likely via PARP, leading to intracellular Ca²⁺ increase and necrotic cell death. Abbreviations: ADPR, ADP-ribose; CDC, chenodeoxycholate; Drp1, dynamin-related protein 1; NOX, NADPH oxidase; PARP, poly(ADPR) polymerase; ROS, reactive oxygen species; STZ, streptozotocin.

Fig. 7

TRPM2-mediated signalling pathways in oxidative stress-induced kidney cell death associated with acute kidney injury and chronic kidney disease. (A) Ischemia/reperfusion-induced kidney cell death associated with acute kidney injury. Exposure to transient ischemia followed by reperfusion increases RAC1 activity that stimulates NOX activation and NOX-mediated ROS production, activation of PARP and the TRPM2 channel. TRPM2 channel activation leads to intracellular Ca²⁺ increase, downregulation of anti-apoptotic proteins (Bcl-2 and Bcl-xL) and activation of caspase-3 and caspase-9 to trigger apoptosis. (B) Albumin-induced cell death in cortical collecting duct cells related to chronic kidney disease, based on examining BSA-induced cell death in mpkCCD_c14 murine cortical collecting duct cells. Exposure to BSA increases ROS production and reduces antioxidant capacity of the cell by downregulating GPx and GSH, increasing intracellular ROS level. PARP-dependent TRPM2 channel activation results in intracellular Ca²⁺ increase, contributing to mitochondrial dysfunction, activation of caspase-3 and caspase-9 and inducing apoptotic cell death. Abbreviations: ADPR, ADP-ribose; BSA, bovine serum albumin; GPx, glutathione peroxidase; GSH, glutathione; I/R, ischemia/reperfusion; NOX, NADPH oxidase; PARP, poly(ADPR) polymerase; ROS, reactive oxygen species.

Fig. 8

TRPM2-mediated signalling pathways in oxidative stress-induced hepatocyte death associated with acetaminophen overdose-induced liver damage. Exposure to high concentrations of acetaminophen leads to OS by increasing ROS production in hepatocytes, and subsequent PARP-dependent TRPM2 channel activation and intracellular Ca²⁺ increase. Ca²⁺ activates CaMKII that in turn phosphorylates BECN1 protein, thereby reducing autophagy and stimulating apoptosis. Abbreviations: ADPR, ADP-ribose; BECN1, Beclin-1; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; PARP, poly(ADPR) polymerase; ROS, reactive oxygen species.