TRPM2 in ischemic stroke: Structure, molecular mechanisms, and drug intervention

Abstract

Ischemic stroke has a high lethality rate worldwide, and novel treatments are limited. Calcium overload is considered to be one of the mechanisms of cerebral ischemia. Transient receptor potential melastatin 2 (TRPM2) is a reactive oxygen species (ROS)-sensitive calcium channel. Cerebral ischemia-induced TRPM2 activation triggers abnormal intracellular Ca 2+ accumulation and cell death, which in turn causes irreversible brain damage. Thus, TRPM2 has emerged as a new therapeutic target for ischemic stroke. This review provides data on the expression, structure, and function of TRPM2 and illustrates its cellular and molecular mechanisms in ischemic stroke. Natural and synthetic TRPM2 inhibitors (both specific and nonspecific) are also summarized. The three-dimensional protein structure of TRPM2 has been identified, and we speculate that molecular simulation techniques will be essential for developing new drugs that block TRPM2 channels. These insights about TRPM2 may be the key to find potent therapeutic approaches for the treatment of ischemic stroke.

Cellular and Molecular Targets for Non-Invasive, Non-Pharmacological Therapeutic/Rehabilitative Interventions in Acute Ischemic Stroke

“…Interestingly, the inhibition of such Zn 2+ signaling significantly attenuates ROS-induced neuronal death. Thus, these data show the significant role of TRPM2 in the intracellular Zn 2+ homeostasis, lysosomal, and mitochondrial functions in ROS-induced neuronal death [30].…”

“…These results support a key role for TRPM2 in coupling PKC/NOX-mediated ROS generation, which causes subsequent positive feedback loops for ROS-induced delayed cell death. [30].…”

TRPM2 Non-Selective Cation Channels in Liver Injury Mediated by Reactive Oxygen Species

“…In principle, the biochemical pathways involved in the initiation and progression of ischemia–reperfusion injury in liver are likely similar to those involved in other well-studied examples of organ ischemia–reperfusion injury, including brain, kidney, and heart [ 22 , 23 , 24 , 25 , 28 ]. Ca 2+ entry via TRPM2 channels in the plasma membrane has been shown to be an important component of the mechanisms responsible for ischemia–reperfusion injury in brain and kidney [ 22 , 24 , 25 ].…”

“…Although direct experiments involving the measurement of intracellular calcium in liver cells during ischemia and reperfusion are somewhat limited, no substantial increases in mitochondrial or cytoplasmic Ca 2+ concentrations in hepatocytes during the ischemic phase have so far been observed [78]. In principle, the biochemical pathways involved in the initiation and progression of ischemia-reperfusion injury in liver are likely similar to those involved in other well-studied examples of organ ischemia-reperfusion injury, including brain, kidney, and heart [22][23][24][25]28]. Ca 2+ entry via TRPM2 channels in the plasma membrane has been shown to be an important component of the mechanisms responsible for ischemia-reperfusion injury in brain and kidney [22,24,25].…”

“…On the basis of studies to date, one of the most important of these is the transient receptor potential melastatin (TRPM2) non-selective cation channel, which facilitates the entry of Ca 2+ and Na + [ 19 , 20 , 21 ]. TRPM2 channels have been shown to play important roles in mediating cell death and injury in many organs and cell types [ 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. These include paracetamol-induced liver toxicity and liver ischemia and reperfusion injury [ 15 , 29 , 30 , 31 , 32 ].…”