Ion channel activation upon ligand gating triggers a myriad of biological events and,therefore,evolution of ligand gating mechanism is of fundamental importance.TRPM2,a typical ancient ion channel,is activated by aden...Ion channel activation upon ligand gating triggers a myriad of biological events and,therefore,evolution of ligand gating mechanism is of fundamental importance.TRPM2,a typical ancient ion channel,is activated by adenosine diphosphate ribose(ADPR)and calcium and its activation has evolved from a simple mode in invertebrates to a more complex one in vertebrates,but the evolutionary process is still unknown.Molecular evolutionary analysis of TRPM2s from more than 280 different animal species has revealed that,the C-terminal NUDT9-H domain has evolved from an enzyme to a ligand binding site for activation,while the N-terminal MHR domain maintains a conserved ligand binding site.Calcium gating pattern has also evolved,from one Ca^(2+)-binding site as in sea anemones to three sites as in human.Importantly,we identified a new group represented by olTRPM2,which has a novel gating mode and fills the missing link of the channel gating evolution.We conclude that the TRPM2 ligand binding or activation mode evolved through at least three identifiable stages in the past billion years from simple to complicated and coordinated.Such findings benefit the evolutionary investigations of other channels and proteins.展开更多
The wound is induced by several mechanical and metabolic factors.In the etiology of the wound recovery,excessive oxidative stress,calcium ion(Ca^(2+))influx,and apoptosis have important roles.Ca^(2+)-permeable TRPM2 c...The wound is induced by several mechanical and metabolic factors.In the etiology of the wound recovery,excessive oxidative stress,calcium ion(Ca^(2+))influx,and apoptosis have important roles.Ca^(2+)-permeable TRPM2 channel is activated by oxidative stress.Protective roles of Hypericum perforatum extract(HP)on the mechanical nerve injury-induced apoptosis and oxidative toxicity through regulation of TRPM2 in the experimental animals were recently reported.The potential protective roles in HP treatment were evaluated on the TRPM2-mediated cellular oxidative toxicity in the renal epithelium(MPK)cells.The cells were divided into three groups as control,wound,and wound+HP treatment(75μM for 72 h).Wound diameters were more importantly decreased in the wound+HP group than in the wound group.In addition,the results of laser confocal microscopy analyses indicated protective roles of HP and TRPM2 antagonists(N-(p-Amylcinnamoyl)anthranilic acid and 2-aminoethyl diphenylborinate)against the wound-induced increase of Ca^(2+) influx and mitochondrial ROS production.The wound-induced increase of early(annexin V-FITC)apoptosis and late(propidium iodide)apoptosis were also decreased in the cells by the HP treatment.In conclusion,HP treatment acted protective effects against wound-mediated oxidative cell toxicity and apoptosis through TRPM2 inhibition.These effects may be attributed to their potent antioxidant effect.展开更多
A protective action of melatonin(MELAT)on docetaxel(DCT)-induced inflammation,apoptosis,and reactive free oxygen radical(fROS)generation values via blocking of TRPM2 calcium-permeable channel was investigated in diffe...A protective action of melatonin(MELAT)on docetaxel(DCT)-induced inflammation,apoptosis,and reactive free oxygen radical(fROS)generation values via blocking of TRPM2 calcium-permeable channel was investigated in different cells except for laryngo-tracheal epithelial(LT-Epi)cells.Hence,the protective action ofMELAT on DCT-induced oxidative toxicity and inflammation in LT-Epi tissue and cells of mice were investigated in the current study.MELAT treatment ameliorated DCTinduced mitochondrial ROS in the LT-Epi cells by reducing the generation of fROS(cytosolic and mitochondrial),lipid peroxidation,and depolarization of the mitochondrial membrane,while increasing reduced glutathione(GSH),GSH peroxidase,and total antioxidant status.In addition,DCT-induced increases of cytokine(IL-1β,IL-6,and TNF-α)generations were also diminished in the LT-Epi tissue by MELAT treatment.Furthermore,MELAT treatment increased viability and count of the cells followed by decreasing levels of cell death,caspase-3,and-9.The TRPM2 activity was also reduced by MELAT and TRPM2 channel blocker(ACA)treatments.In conclusion,MELAT modulated the increase of DCT-induced LT-Epi cell death by inhibiting mitochondrial oxidative stress and TRPM2 channel activity.Hence,DCTcaused side cell death,oxidant,and inflammatory actions in the LT-Epi were diminished via the treatment of MELAT.展开更多
基金supported by the National Natural Science Foundation of China(82030108,31872796,32071102,and 32000707)the Zhejiang Provincial Natural Science Foundation of China(LD24H090004,R16H090001,LQ20H160039,LTY21H160003,and LY19B020013)+3 种基金National Major Scientific and Technological Special Project for“Significant New Drugs Development”(2018ZX09711001-004-005)Zhejiang Association for Science and Technology Talent Cultivation Project(CTZB-2020080127)the East-West Cooperation Project(2019BFH02003)the MOE Frontier Science Center for Brain Science&Brain-Machine Integration,Zhejiang University。
文摘Ion channel activation upon ligand gating triggers a myriad of biological events and,therefore,evolution of ligand gating mechanism is of fundamental importance.TRPM2,a typical ancient ion channel,is activated by adenosine diphosphate ribose(ADPR)and calcium and its activation has evolved from a simple mode in invertebrates to a more complex one in vertebrates,but the evolutionary process is still unknown.Molecular evolutionary analysis of TRPM2s from more than 280 different animal species has revealed that,the C-terminal NUDT9-H domain has evolved from an enzyme to a ligand binding site for activation,while the N-terminal MHR domain maintains a conserved ligand binding site.Calcium gating pattern has also evolved,from one Ca^(2+)-binding site as in sea anemones to three sites as in human.Importantly,we identified a new group represented by olTRPM2,which has a novel gating mode and fills the missing link of the channel gating evolution.We conclude that the TRPM2 ligand binding or activation mode evolved through at least three identifiable stages in the past billion years from simple to complicated and coordinated.Such findings benefit the evolutionary investigations of other channels and proteins.
文摘The wound is induced by several mechanical and metabolic factors.In the etiology of the wound recovery,excessive oxidative stress,calcium ion(Ca^(2+))influx,and apoptosis have important roles.Ca^(2+)-permeable TRPM2 channel is activated by oxidative stress.Protective roles of Hypericum perforatum extract(HP)on the mechanical nerve injury-induced apoptosis and oxidative toxicity through regulation of TRPM2 in the experimental animals were recently reported.The potential protective roles in HP treatment were evaluated on the TRPM2-mediated cellular oxidative toxicity in the renal epithelium(MPK)cells.The cells were divided into three groups as control,wound,and wound+HP treatment(75μM for 72 h).Wound diameters were more importantly decreased in the wound+HP group than in the wound group.In addition,the results of laser confocal microscopy analyses indicated protective roles of HP and TRPM2 antagonists(N-(p-Amylcinnamoyl)anthranilic acid and 2-aminoethyl diphenylborinate)against the wound-induced increase of Ca^(2+) influx and mitochondrial ROS production.The wound-induced increase of early(annexin V-FITC)apoptosis and late(propidium iodide)apoptosis were also decreased in the cells by the HP treatment.In conclusion,HP treatment acted protective effects against wound-mediated oxidative cell toxicity and apoptosis through TRPM2 inhibition.These effects may be attributed to their potent antioxidant effect.
基金supported by BSN Health,Analyses,Innovation,Consultancy,Organization,Agriculture Ltd.,Göller Bölgesi Teknokenti,Isparta,Turkey(Project No.2018-09 by Dr.SGK).
文摘A protective action of melatonin(MELAT)on docetaxel(DCT)-induced inflammation,apoptosis,and reactive free oxygen radical(fROS)generation values via blocking of TRPM2 calcium-permeable channel was investigated in different cells except for laryngo-tracheal epithelial(LT-Epi)cells.Hence,the protective action ofMELAT on DCT-induced oxidative toxicity and inflammation in LT-Epi tissue and cells of mice were investigated in the current study.MELAT treatment ameliorated DCTinduced mitochondrial ROS in the LT-Epi cells by reducing the generation of fROS(cytosolic and mitochondrial),lipid peroxidation,and depolarization of the mitochondrial membrane,while increasing reduced glutathione(GSH),GSH peroxidase,and total antioxidant status.In addition,DCT-induced increases of cytokine(IL-1β,IL-6,and TNF-α)generations were also diminished in the LT-Epi tissue by MELAT treatment.Furthermore,MELAT treatment increased viability and count of the cells followed by decreasing levels of cell death,caspase-3,and-9.The TRPM2 activity was also reduced by MELAT and TRPM2 channel blocker(ACA)treatments.In conclusion,MELAT modulated the increase of DCT-induced LT-Epi cell death by inhibiting mitochondrial oxidative stress and TRPM2 channel activity.Hence,DCTcaused side cell death,oxidant,and inflammatory actions in the LT-Epi were diminished via the treatment of MELAT.
