Journal articles on the topic 'TRPM2 channel'
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1
Yang, Xiao-Ru, Mo-Jun Lin, Lionel S. McIntosh, and James S. K. Sham. "Functional expression of transient receptor potential melastatin- and vanilloid-related channels in pulmonary arterial and aortic smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 290, no. 6 (June 2006): L1267—L1276. http://dx.doi.org/10.1152/ajplung.00515.2005.
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Transient receptor potential melastatin- (TRPM) and vanilloid-related (TRPV) channels are nonselective cation channels pertinent to diverse physiological functions. Multiple TRPM and TRPV channel subtypes have been identified and cloned in different tissues. However, their information in vascular tissue is scant. In this study, we sought to identify TRPM and TRPV channel subtypes expressed in rat deendothelialized intralobar pulmonary arteries (PAs) and aorta. With RT-PCR, mRNA of TRPM2, TRPM3, TRPM4, TRPM7, and TRPM8 of TRPM family and TRPV1, TRPV2, TRPV3, and TRPV4 of TRPV family were detected in both PAs and aorta. Quantitative real-time RT-PCR showed that TRPM8 and TRPV4 were the most abundantly expressed TRPM and TRPV subtypes, respectively. Moreover, Western blot analysis verified expression of TRPM2, TRPM8, TRPV1, and TRPV4 proteins in both types of vascular tissue. To examine the functional activities of these channels, we monitored intracellular Ca2+ transients ([Ca2+]i) in pulmonary arterial smooth muscle cells (PASMCs) and aortic smooth muscle cells (ASMCs). The TRPM8 agonist menthol (300 μM) and the TRPV4 agonist 4α-phorbol 12,13-didecanoate (1 μM) evoked significant increases in [Ca2+]i in PASMCs and ASMCs. These Ca2+ responses were abolished in the absence of extracellular Ca2+ or the presence of 300 μM Ni2+ but were unaffected by 1 μM nifedipine, suggesting Ca2+ influx via nonselective cation channels. Hence, for the first time, our results indicate that multiple functional TRPM and TRPV channels are coexpressed in rat intralobar PAs and aorta. These novel Ca2+ entry pathways may play important roles in the regulation of pulmonary and systemic circulation.
2
Marshall-Gradisnik, Sonya M., Peter Smith, Ekua W. Brenu, Bernd Nilius, Sandra B. Ramos, and Donald R. Staines. "Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients." Immunology and Immunogenetics Insights 7 (January 2015): III.S25147. http://dx.doi.org/10.4137/iii.s25147.
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Background The transient receptor potential (TRP) superfamily in humans comprises 27 cation channels with permeability to monovalent and divalent cations. These channels are widely expressed within humans on cells and tissues and have significant sensory and regulatory roles on most physiological functions. Chronic fatigue syndrome (CFS) is an unexplained disorder with multiple physiological impairments. OBJECTIVES The purpose of this study was to determine the role of TRPs in CFS. Methods The study comprised 115 CFS patients (age = 48.68 ± 1.06 years) and 90 nonfatigued controls (age = 46.48 ± 1.22 years). CFS patients were defined according to the 1994 Center for Disease Prevention and Control criteria for CFS. A total of 240 single nucleotide polymorphisms (SNPs) for 21 mammalian TRP ion channel genes ( TRPA1, TRPC1, TRPC2, TRPC3, TRPC4, TRPC6, TRPC7, TRPM1, TRPM2, TRPM3, TRPM4, TRPM5, TRPM6, TRPM7, TRPM8, TRPV1, TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6) were examined via the Agena Biosciences iPLEX Gold assay. Statistical analysis was performed using the PLINK analysis software. Results Thirteen SNPs were significantly associated with CFS patients compared with the controls. Nine of these SNPs were associated with TRPM3 (rs12682832; P < 0.003, rs11142508; P < 0.004, rs1160742; P < 0.08, rs4454352; P < 0.013, rs1328153; P < 0.013, rs3763619; P < 0.014, rs7865858; P ≤ 0.021, rs1504401; P ≤ 0041, rs10115622; P ≤ 0.050), while the remainder were associated with TRPA1 (rs2383844; P ≤ 0.040, rs4738202; P ≤ 0.018) and TRPC4 (rs6650469; P ≤ 0.016, rs655207; P ≤ 0.018). Conclusion The data from this pilot study suggest an association between TRP ion channels, predominantly TRPM3 and CFS. This and other TRPs identified may contribute to the etiology and pathomechanism of CFS.
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Lötsch, Jörn, Dario Kringel, Gerd Geisslinger, Bruno G. Oertel, Eduard Resch, and Sebastian Malkusch. "Machine-Learned Association of Next-Generation Sequencing-Derived Variants in Thermosensitive Ion Channels Genes with Human Thermal Pain Sensitivity Phenotypes." International Journal of Molecular Sciences 21, no. 12 (June 19, 2020): 4367. http://dx.doi.org/10.3390/ijms21124367.
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Genetic association studies have shown their usefulness in assessing the role of ion channels in human thermal pain perception. We used machine learning to construct a complex phenotype from pain thresholds to thermal stimuli and associate it with the genetic information derived from the next-generation sequencing (NGS) of 15 ion channel genes which are involved in thermal perception, including ASIC1, ASIC2, ASIC3, ASIC4, TRPA1, TRPC1, TRPM2, TRPM3, TRPM4, TRPM5, TRPM8, TRPV1, TRPV2, TRPV3, and TRPV4. Phenotypic information was complete in 82 subjects and NGS genotypes were available in 67 subjects. A network of artificial neurons, implemented as emergent self-organizing maps, discovered two clusters characterized by high or low pain thresholds for heat and cold pain. A total of 1071 variants were discovered in the 15 ion channel genes. After feature selection, 80 genetic variants were retained for an association analysis based on machine learning. The measured performance of machine learning-mediated phenotype assignment based on this genetic information resulted in an area under the receiver operating characteristic curve of 77.2%, justifying a phenotype classification based on the genetic information. A further item categorization finally resulted in 38 genetic variants that contributed most to the phenotype assignment. Most of them (10) belonged to the TRPV3 gene, followed by TRPM3 (6). Therefore, the analysis successfully identified the particular importance of TRPV3 and TRPM3 for an average pain phenotype defined by the sensitivity to moderate thermal stimuli.
4
Müller, Isabel, Philipp Alt, Suhasini Rajan, Lena Schaller, Fabienne Geiger, and Alexander Dietrich. "Transient Receptor Potential (TRP) Channels in Airway Toxicity and Disease: An Update." Cells 11, no. 18 (September 17, 2022): 2907. http://dx.doi.org/10.3390/cells11182907.
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Our respiratory system is exposed to toxicants and pathogens from both sides: the airways and the vasculature. While tracheal, bronchial and alveolar epithelial cells form a natural barrier in the airways, endothelial cells protect the lung from perfused toxic compounds, particulate matter and invading microorganism in the vascular system. Damages induce inflammation by our immune response and wound healing by (myo)fibroblast proliferation. Members of the transient receptor potential (TRP) superfamily of ion channel are expressed in many cells of the respiratory tract and serve multiple functions in physiology and pathophysiology. TRP expression patterns in non-neuronal cells with a focus on TRPA1, TRPC6, TRPM2, TRPM5, TRPM7, TRPV2, TRPV4 and TRPV6 channels are presented, and their roles in barrier function, immune regulation and phagocytosis are summarized. Moreover, TRP channels as future pharmacological targets in chronic obstructive pulmonary disease (COPD), asthma, cystic and pulmonary fibrosis as well as lung edema are discussed.
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Saito, Shigeru, and Ryuzo Shingai. "Evolution of thermoTRP ion channel homologs in vertebrates." Physiological Genomics 27, no. 3 (December 2006): 219–30. http://dx.doi.org/10.1152/physiolgenomics.00322.2005.
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In mammalian thermosensation, nine temperature-sensitive ion channels that are activated by distinct temperature thresholds have been identified as thermosensors. These ion channels belong to the transient receptor potential (TRP) superfamily and are referred to as “thermoTRPs” (TRPV1, TRPV2, TRPV3, TRPV4, TRPM2, TRPM4, TRPM5, TRPM8, and TRPA1). To elucidate the evolutionary processes of thermoTRPs, we conducted comprehensive searches for mammalian thermoTRP gene homologs in the draft genome sequences of chicken ( Gallus gallus), western clawed frog ( Xenopus tropicalis), zebrafish ( Danio rerio), and pufferfish ( Fugu rubripes). Newly identified homologs were compared with known thermoTRPs, and phylogenetic analyses were conducted. Our comparative analyses revealed that most of the mammalian thermo-TRP members already existed in the common ancestor of fishes and tetrapods. Tetrapods shared almost the same repertoire, except that the western clawed frog expanded TRPV4s (six copies) and TRPM8s (two copies), which were diversified considerably. Comparisons of nonsynonymous and synonymous substitution rates among TRPV4s suggested that one copy of the TRPV4 channel in the western clawed frog retained its original function, while the other copies diversified and obtained slightly different properties. In fish lineages, several members of thermo-TRPs have duplicated in the whole genome duplication occurred in the ancestral ray-finned fish; however, some of the copies have subsequently been lost. Furthermore, fishes do not possess the three members of thermoTRPs existed in mammals, e.g., thermoTRPs activated by noxious heat, warm, and cool temperatures. Our results suggest that thermosensation mechanisms have changed through vertebrate evolution with respect to thermosensor repertoires.
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Mei, Zhu-Zhong, Hong-Ju Mao, and Lin-Hua Jiang. "Conserved cysteine residues in the pore region are obligatory for human TRPM2 channel function." American Journal of Physiology-Cell Physiology 291, no. 5 (November 2006): C1022—C1028. http://dx.doi.org/10.1152/ajpcell.00606.2005.
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TRPM2 proteins belong to the melastatin-related transient receptor potential or TRPM subfamily and form Ca2+-permeable cationic channels activated by intracellular adenosine diphosphoribose (ADPR). The TRPM2 channel subunit, like all its close relatives, is structurally homologous to the well-characterized voltage-gated potassium channel subunits, each containing six transmembrane segments and a putative pore loop between the fifth and sixth segments. Nevertheless, the structural elements determining the TRPM2 channel functions are still not well understood. In this study, we investigated the functional role of two conserved cysteine residues (at positions 996 and 1008) in the putative pore region of the human TRPM2 by site-directed mutagenesis, combined with electrophysiological and biochemical approaches. Expression of wild-type hTRPM2 channels in human embryonic kidney (HEK-293) cells resulted in robust ADPR-evoked currents. Substitution of cysteine with alanine or serine generated mutant channels that failed to be activated by ADPR. Furthermore, experiments done by Western blot analysis, immunocytochemistry, biotin labeling, and coimmunoprecipitation techniques showed no obvious changes in protein expression, trafficking or membrane localization, and the ability to interact with neighboring subunits that is required for channel assembly. Coexpression of wild-type and mutant subunits significantly reduced the ADPR-evoked currents; for the combination of wild-type and C996S mutant subunits, the reduction was ∼95%, indicating that incorporation of one or more nonfunctional C996S subunits leads to the loss of channel function. These results taken together suggest that the cysteine residues in the pore region are obligatory for TRPM2 channel function.
7
Du Preez, Stanley, Natalie Eaton-Fitch, Helene Cabanas, Donald Staines, and Sonya Marshall-Gradisnik. "Characterization of IL-2 Stimulation and TRPM7 Pharmacomodulation in NK Cell Cytotoxicity and Channel Co-Localization with PIP2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients." International Journal of Environmental Research and Public Health 18, no. 22 (November 12, 2021): 11879. http://dx.doi.org/10.3390/ijerph182211879.
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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystemic disorder responsible for significant disability. Although a unifying etiology for ME/CFS is uncertain, impaired natural killer (NK) cell cytotoxicity represents a consistent and measurable feature of this disorder. Research utilizing patient-derived NK cells has implicated dysregulated calcium (Ca2+) signaling, dysfunction of the phosphatidylinositol-4,5-bisphosphate (PIP2)-dependent cation channel, transient receptor potential melastatin (TRPM) 3, as well as altered surface expression patterns of TRPM3 and TRPM2 in the pathophysiology of ME/CFS. TRPM7 is a related channel that is modulated by PIP2 and participates in Ca2+ signaling. Though TRPM7 is expressed on NK cells, the role of TRPM7 with IL-2 and intracellular signaling mechanisms in the NK cells of ME/CFS patients is unknown. This study examined the effect of IL-2 stimulation and TRPM7 pharmacomodulation on NK cell cytotoxicity using flow cytometric assays as well as co-localization of TRPM7 with PIP2 and cortical actin using confocal microscopy in 17 ME/CFS patients and 17 age- and sex-matched healthy controls. The outcomes of this investigation are preliminary and indicate that crosstalk between IL-2 and TRMP7 exists. A larger sample size to confirm these findings and characterization of TRPM7 in ME/CFS using other experimental modalities are warranted.
8
Szollosi, Andras. "Two Decades of Evolution of Our Understanding of the Transient Receptor Potential Melastatin 2 (TRPM2) Cation Channel." Life 11, no. 5 (April 27, 2021): 397. http://dx.doi.org/10.3390/life11050397.
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The transient receptor potential melastatin (TRPM) family belongs to the superfamily of TRP ion channels. It consists of eight family members that are involved in a plethora of cellular functions. TRPM2 is a homotetrameric Ca2+-permeable cation channel activated upon oxidative stress and is important, among others, for body heat control, immune cell activation and insulin secretion. Invertebrate TRPM2 proteins are channel enzymes; they hydrolyze the activating ligand, ADP-ribose, which is likely important for functional regulation. Since its cloning in 1998, the understanding of the biophysical properties of the channel has greatly advanced due to a vast number of structure–function studies. The physiological regulators of the channel have been identified and characterized in cell-free systems. In the wake of the recent structural biochemistry revolution, several TRPM2 cryo-EM structures have been published. These structures have helped to understand the general features of the channel, but at the same time have revealed unexplained mechanistic differences among channel orthologues. The present review aims at depicting the major research lines in TRPM2 structure-function. It discusses biophysical properties of the pore and the mode of action of direct channel effectors, and interprets these functional properties on the basis of recent three-dimensional structural models.
9
Wang, Longfei, Tian-Min Fu, Yiming Zhou, Shiyu Xia, Anna Greka, and Hao Wu. "Structures and gating mechanism of human TRPM2." Science 362, no. 6421 (November 22, 2018): eaav4809. http://dx.doi.org/10.1126/science.aav4809.
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Transient receptor potential (TRP) melastatin 2 (TRPM2) is a cation channel associated with numerous diseases. It has a C-terminal NUDT9 homology (NUDT9H) domain responsible for binding adenosine diphosphate (ADP)–ribose (ADPR), and both ADPR and calcium (Ca2+) are required for TRPM2 activation. Here we report cryo–electron microscopy structures of human TRPM2 alone, with ADPR, and with ADPR and Ca2+. NUDT9H forms both intra- and intersubunit interactions with the N-terminal TRPM homology region (MHR1/2/3) in the apo state but undergoes conformational changes upon ADPR binding, resulting in rotation of MHR1/2 and disruption of the intersubunit interaction. The binding of Ca2+ further engages transmembrane helices and the conserved TRP helix to cause conformational changes at the MHR arm and the lower gating pore to potentiate channel opening. These findings explain the molecular mechanism of concerted TRPM2 gating by ADPR and Ca2+ and provide insights into the gating mechanism of other TRP channels.
10
Nilius, B., F. Mahieu, Y. Karashima, and T. Voets. "Regulation of TRP channels: a voltage–lipid connection." Biochemical Society Transactions 35, no. 1 (January 22, 2007): 105–8. http://dx.doi.org/10.1042/bst0350105.
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TRP (transient receptor potential) channels respond to a plethora of stimuli in a fine-tuned manner. We show here that both membrane potential and the level of PI (phosphatidylinositol) phosphates are efficient regulators of TRP channel gating. Recent work has shown that this regulation applies to several members of the TRPV (TRP vanilloid) subfamily (TRPV1 and TRPV5) and the TRPM (TRP melastatin) subfamily (TRPM4/TRPM5/TRPM7/TRPM8), whereas regulation of members of the TRPC subfamily is still disputed. The mechanism whereby PIP2 (PI 4,5-bisphosphate) acts on TRPM4, a Ca2+- and voltage-activated channel, is shown in detail in this paper: (i) PIP2 may bind directly to the channel, (ii) PIP2 induces sensitization to activation by Ca2+, and (iii) PIP2 shifts the voltage dependence towards negative and physiologically more meaningful potentials. A PIP2-binding pocket seems to comprise a part of the TRP domain and especially pleckstrin homology domains in the C-terminus.
11
Song, Yumei, Ben Buelow, Anne-Laure Perraud, and Andrew M. Scharenberg. "Development and Validation of a Cell-Based High-Throughput Screening Assay for TRPM2 Channel Modulators." Journal of Biomolecular Screening 13, no. 1 (November 26, 2007): 54–61. http://dx.doi.org/10.1177/1087057107310986.
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TRPM2 is a member of the transient receptor potential melastatin (TRPM)—related ion channel family. The activation of TRPM2 induced by oxidative/nitrosative stress leads to an increase in intracellular free Ca2+. Although further progress in understanding TRPM2's role in cell and organism physiology would be facilitated by isolation of compounds able to specifically modulate its function in primary cells or animal models, no cell-based assays for TRPM2 function well suited for high-throughput screening have yet been described. Here, a novel suspension B lymphocyte cell line stably expressing TRPM2 was used to develop a cell-based assay. The assay uses the Ca2+-sensitive fluorescence dye, Fluo-4 NW (no wash), to measure TRPM2-dependent Ca2+ transients induced by H2O2 and N-methyl-N′-nitrosoguanidine in a 96-well plate format. Assay performance was evaluated by statistical analysis of the Z′ factor value and was consistently greater than 0.5 under optimal conditions, suggesting that the assay is very robust. For assay validation, the effects of known inhibitors of TRPM2 and TRPM2 gating secondary messenger production were determined. Overall, the authors have developed a cell-based assay that may be used to identify TRPM2 ion channel modulators from large compound libraries. ( Journal of Biomolecular Screening 2008:54-61)
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Chen, Shu-jen, Wenyi Zhang, Qin Tong, Kathleen Conrad, Iwona Hirschler-Laszkiewicz, Michael Bayerl, Jason K. Kim, Joseph Y. Cheung, and Barbara A. Miller. "Role of TRPM2 in cell proliferation and susceptibility to oxidative stress." American Journal of Physiology-Cell Physiology 304, no. 6 (March 15, 2013): C548—C560. http://dx.doi.org/10.1152/ajpcell.00069.2012.
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The transient receptor potential (TRP) channel TRPM2 is an ion channel that modulates cell survival. We report here that full-length (TRPM2-L) and short (TRPM2-S) isoform expression was significantly increased in human neuroblastoma compared with adrenal gland. To differentiate the roles of TRPM2-L and TRPM2-S in cell proliferation and survival, we established neuroblastoma SH-SY5Y cell lines stably expressing either TRPM2 isoform or empty vector. Cells expressing TRPM2-S showed significantly enhanced proliferation, downregulation of phosphatase and tensin homolog (PTEN), and increased protein kinase B (Akt) phosphorylation and cell surface glucose transporter 1 (Glut1) compared with cells expressing TRPM2-L or empty vector. ERK phosphorylation was increased, and forkhead box O 3a (FOXO3a) levels were decreased. Inhibitor studies demonstrated that enhanced proliferation was dependent on phosphatidylinositol 3-kinase/Akt, ERK, and NADPH oxidase activation. On the other hand, TRPM2-S-expressing cells were significantly more susceptible to cell death induced by low H2O2concentrations (50–100 μM), whereas TRPM2-L-expressing cells were protected. This was associated with a significant increase in FOXO3a, MnSOD (SOD2), and membrane Glut1 in TRPM2-L-expressing cells compared with TRPM2-S expressing cells. We conclude that TRPM2 channels occupy a key role in cell proliferation and survival following oxidative stress in neuroblastoma. Our results suggest that overexpression of TRPM2-S results in increased proliferation through phosphatidylinositol 3-kinase/Akt and ERK pathways, while overexpression of TRPM2-L confers protection against oxidative stress-induced cell death through FOXO3a and SOD. TRPM2 channels may represent a novel future therapeutic target in diseases involving oxidative stress.
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Du, Jianyang, Jia Xie, and Lixia Yue. "Modulation of TRPM2 by acidic pH and the underlying mechanisms for pH sensitivity." Journal of General Physiology 134, no. 6 (November 16, 2009): 471–88. http://dx.doi.org/10.1085/jgp.200910254.
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TRPM2 is a Ca2+-permeable nonselective cation channel that plays important roles in oxidative stress–mediated cell death and inflammation processes. However, how TRPM2 is regulated under physiological and pathological conditions is not fully understood. Here, we report that both intracellular and extracellular protons block TRPM2 by inhibiting channel gating. We demonstrate that external protons block TRPM2 with an IC50 of pHo = 5.3, whereas internal protons inhibit TRPM2 with an IC50 of pHi = 6.7. Extracellular protons inhibit TRPM2 by decreasing single-channel conductance. We identify three titratable residues, H958, D964, and E994, at the outer vestibule of the channel pore that are responsible for pHo sensitivity. Mutations of these residues reduce single-channel conductance, decrease external Ca2+ ([Ca2+]o) affinity, and inhibit [Ca2+]o-mediated TRPM2 gating. These results support the following model: titration of H958, D964, and E994 by external protons inhibits TRPM2 gating by causing conformation change of the channel, and/or by decreasing local Ca2+ concentration at the outer vestibule, therefore reducing [Ca2+]o permeation and inhibiting [Ca2+]o-mediated TRPM2 gating. We find that intracellular protons inhibit TRPM2 by inducing channel closure without changing channel conductance. We identify that D933 located at the C terminus of the S4-S5 linker is responsible for intracellular pH sensitivity. Replacement of Asp933 by Asn933 changes the IC50 from pHi = 6.7 to pHi = 5.5. Moreover, substitution of Asp933 with various residues produces marked changes in proton sensitivity, intracellular ADP ribose/Ca2+ sensitivity, and gating profiles of TRPM2. These results indicate that D933 is not only essential for intracellular pH sensitivity, but it is also crucial for TRPM2 channel gating. Collectively, our findings provide a novel mechanism for TRPM2 modulation as well as molecular determinants for pH regulation of TRPM2. Inhibition of TRPM2 by acidic pH may represent an endogenous mechanism governing TRPM2 gating and its physiological/pathological functions.
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Ahn, C., E. J. Hong, and E. B. Jeung. "129 UTERINE EXPRESSION OF TRANSIENT RECEPTOR POTENTIAL MELASTATIN 2 CHANNEL AND ITS REGULATION BY SEX STEROID HORMONES." Reproduction, Fertility and Development 26, no. 1 (2014): 178. http://dx.doi.org/10.1071/rdv26n1ab129.
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The transient potential receptor (TRP) channels are membrane-binding proteins that are non-selectively permeable for cations, such as Ca2+ and Mg2+, in numerous mammalian cells. The extracellular or intracellular ions play key roles in physiological function, including muscle contraction, cytokine production, insulin release, and apoptosis. Although TRPM channels have been implicated in the brain, bone marrow, and spleen, the presence of TRPM2 has been reported in the endometrium of the uterus. To determine whether expression of the TRPM2 gene in the uterus is due to gonadal steroid hormones or a hormone-independent effect, the uterine TRPM2 gene was monitored in mature rats during the oestrous cycle and in immature rats after treatment with gonadal steroid oestrogen (E2), progesterone (P4) with/without their antagonist, ICI 182,780, and RU486. Dramatic induction of the level of TRPM2 mRNA occurs at proestrus, followed by a drop to baseline levels at metestrus, and its level is restored at diestrus. Furthermore, the immune-reactive TRPM2 is observed in stromal cells of the myometrium and endometrium, and changes during the oestrus cycle. In addition, E2-induced TRPM2 is inhibited by co-treatment with P4. Taken together, these results imply that TRPM2 expression levels in the uterus are regulated by gonadal steroid hormones E2 and P4. Results of this study suggest possible involvement of TRPM2 in reproductive function during the oestrous cycle in female rats.
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Jia, Jia, Saurabh Verma, Shin Nakayama, Nidia Quillinan, Marjorie R. Grafe, Patricia D. Hurn, and Paco S. Herson. "Sex Differences in Neuroprotection Provided by Inhibition of TRPM2 Channels following Experimental Stroke." Journal of Cerebral Blood Flow & Metabolism 31, no. 11 (May 18, 2011): 2160–68. http://dx.doi.org/10.1038/jcbfm.2011.77.
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The calcium-permeable transient receptor potential M2 (TRPM2) ion channel is activated following oxidative stress and has been implicated in ischemic damage; however, little experimental evidence exists linking TRPM2 channel activation to damage following cerebral ischemia. We directly assessed the involvement of TRPM2 channels in ischemic brain injury using pharmacological inhibitors and short-hairpin RNA (shRNA)-mediated knockdown of TRPM2 expression. Each of the four TRPM2 inhibitors tested provided significant protection to male neurons following in vitro ischemia (oxygen–glucose deprivation, OGD), while having no effect in female neurons. Similarly, TRPM2 knockdown by TRPM2 shRNA resulted in significantly reduced neuronal cell death following OGD only in male neurons. The TRPM2 inhibitor clotrimazole reduced infarct volume in male mice, while having no effect on female infarct volume. Finally, intrastriatal injection of lentivirus expressing shRNA against TRPM2 resulted in significantly smaller striatal infarcts only in male mice following middle cerebral artery occlusion, having no significant effect in female mice. Data presented in the current study demonstrate that TRPM2 inhibition and knockdown preferentially protects male neurons and brain against ischemia in vitro and in vivo, indicating that TRPM2 inhibitors may provide a new therapeutic approach to the treatment of stroke in men.
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Csanády, László, and Beáta Törőcsik. "Four Ca2+ Ions Activate TRPM2 Channels by Binding in Deep Crevices near the Pore but Intracellularly of the Gate." Journal of General Physiology 133, no. 2 (January 26, 2009): 189–203. http://dx.doi.org/10.1085/jgp.200810109.
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TRPM2 is a tetrameric Ca2+-permeable channel involved in immunocyte respiratory burst and in postischaemic neuronal death. In whole cells, TRPM2 activity requires intracellular ADP ribose (ADPR) and intra- or extracellular Ca2+, but the mechanism and the binding sites for Ca2+ activation remain unknown. Here we study TRPM2 gating in inside-out patches while directly controlling intracellular ligand concentrations. Concentration jump experiments at various voltages and Ca2+ dependence of steady-state single-channel gating kinetics provide unprecedented insight into the molecular mechanism of Ca2+ activation. In patches excised from Xenopus laevis oocytes expressing human TRPM2, coapplication of intracellular ADPR and Ca2+ activated ∼50-pS nonselective cation channels; K1/2 for ADPR was ∼1 µM at saturating Ca2+. Intracellular Ca2+ dependence of TRPM2 steady-state opening and closing rates (at saturating [ADPR] and low extracellular Ca2+) reveals that Ca2+ activation is a consequence of tighter binding of Ca2+ in the open rather than in the closed channel conformation. Four Ca2+ ions activate TRPM2 with a Monod-Wymann-Changeux mechanism: each binding event increases the open-closed equilibrium constant ∼33-fold, producing altogether 106-fold activation. Experiments in the presence of 1 mM of free Ca2+ on the extracellular side clearly show that closed channels do not sense extracellular Ca2+, but once channels have opened Ca2+ entering passively through the pore slows channel closure by keeping the “activating sites” saturated, despite rapid continuous Ca2+-free wash of the intracellular channel surface. This effect of extracellular Ca2+ on gating is gradually lost at progressively depolarized membrane potentials, where the driving force for Ca2+ influx is diminished. Thus, the activating sites lie intracellularly from the gate, but in a shielded crevice near the pore entrance. Our results suggest that in intact cells that contain micromolar ADPR a single brief puff of Ca2+ likely triggers prolonged, self-sustained TRPM2 activity.
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Balemans, Dafne, Guy E. Boeckxstaens, Karel Talavera, and Mira M. Wouters. "Transient receptor potential ion channel function in sensory transduction and cellular signaling cascades underlying visceral hypersensitivity." American Journal of Physiology-Gastrointestinal and Liver Physiology 312, no. 6 (June 1, 2017): G635—G648. http://dx.doi.org/10.1152/ajpgi.00401.2016.
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Visceral hypersensitivity is an important mechanism underlying increased abdominal pain perception in functional gastrointestinal disorders including functional dyspepsia, irritable bowel syndrome, and inflammatory bowel disease in remission. Although the exact pathophysiological mechanisms are poorly understood, recent studies described upregulation and altered functions of nociceptors and their signaling pathways in aberrant visceral nociception, in particular the transient receptor potential (TRP) channel family. A variety of TRP channels are present in the gastrointestinal tract (TRPV1, TRPV3, TRPV4, TRPA1, TRPM2, TRPM5, and TRPM8), and modulation of their function by increased activation or sensitization (decreased activation threshold) or altered expression in visceral afferents have been reported in visceral hypersensitivity. TRP channels directly detect or transduce osmotic, mechanical, thermal, and chemosensory stimuli. In addition, pro-inflammatory mediators released in tissue damage or inflammation can activate receptors of the G protein-coupled receptor superfamily leading to TRP channel sensitization and activation, which amplify pain and neurogenic inflammation. In this review, we highlight the present knowledge on the functional roles of neuronal TRP channels in visceral hypersensitivity and discuss the signaling pathways that underlie TRP channel modulation. We propose that a better understanding of TRP channels and their modulators may facilitate the development of more selective and effective therapies to treat visceral hypersensitivity.
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Hecquet, Claudie, and Asrar Malik. "Role of H2O2-activated TRPM2 calcium channel in oxidant-induced endothelial injury." Thrombosis and Haemostasis 101, no. 04 (2009): 619–25. http://dx.doi.org/10.1160/th08-10-0641.
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SummaryThe transient receptor potential (melastatin) 2 (TRPM2), is an oxidant-activated non-selective cation channel that is widely expressed in mammalian tissues including the vascular endothelium. Oxidative stress, through the generation of oxygen meta-bolites including H2O2, stimulates intracellular ADP-ribose formation which, in turn, opens TRPM2 channels. These channels act as an endogenous redox sensor for mediating oxidative stress/ROS-induced Ca2+ entry and the subsequent specific Ca2+-dependent cellular reactions such as endothelial hyper-permeability and apoptosis. This review summarizes recent findings on the mechanism by which oxidants induce TRPM2 activation, the role of these channels in the signalling vascular endothelial dysfunctions, and the modulation of oxidant-induced TRPM2 activation by PKCα and phospho-tyrosine phosphates L1.
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Yang, Wei, Paul T. Manna, Jie Zou, Jianhong Luo, David J. Beech, Asipu Sivaprasadarao, and Lin-Hua Jiang. "Zinc Inactivates Melastatin Transient Receptor Potential 2 Channels via the Outer Pore." Journal of Biological Chemistry 286, no. 27 (May 20, 2011): 23789–98. http://dx.doi.org/10.1074/jbc.m111.247478.
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Zinc ion (Zn2+) is an endogenous allosteric modulator that regulates the activity of a wide variety of ion channels in a reversible and concentration-dependent fashion. Here we used patch clamp recording to study the effects of Zn2+ on the melastatin transient receptor potential 2 (TRPM2) channel. Zn2+ inhibited the human (h) TRPM2 channel currents, and the steady-state inhibition was largely not reversed upon washout and concentration-independent in the range of 30–1000 μm, suggesting that Zn2+ induces channel inactivation. Zn2+ inactivated the channels fully when they conducted inward currents, but only by half when they passed outward currents, indicating profound influence of the permeant ion on Zn2+ inactivation. Alanine substitution scanning mutagenesis of 20 Zn2+-interacting candidate residues in the outer pore region of the hTRPM2 channel showed that mutation of Lys952 in the extracellular end of the fifth transmembrane segment and Asp1002 in the large turret strongly attenuated or abolished Zn2+ inactivation, and mutation of several other residues dramatically changed the inactivation kinetics. The mouse (m) TRPM2 channels were also inactivated by Zn2+, but the kinetics were remarkably slower. Reciprocal mutation of His995 in the hTRPM2 channel and the equivalent Gln992 in the mTRPM2 channel completely swapped the kinetics, but no such opposing effects resulted from exchanging another pair of species-specific residues, Arg961/Ser958. We conclude from these results that Zn2+ inactivates the TRPM2 channels and that residues in the outer pore are critical determinants of the inactivation.
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Morita, Taku, Keiichi Mitsuyama, Hiroshi Yamasaki, Atsushi Mori, Tetsuhiro Yoshimura, Toshihiro Araki, Masaru Morita, et al. "Gene Expression of Transient Receptor Potential Channels in Peripheral Blood Mononuclear Cells of Inflammatory Bowel Disease Patients." Journal of Clinical Medicine 9, no. 8 (August 14, 2020): 2643. http://dx.doi.org/10.3390/jcm9082643.
Full textAbstract:
We examined the expression profile of transient receptor potential (TRP) channels in peripheral blood mononuclear cells (PBMCs) from patients with inflammatory bowel disease (IBD). PBMCs were obtained from 41 ulcerative colitis (UC) patients, 34 Crohn’s disease (CD) patients, and 30 normal subjects. mRNA levels of TRP channels were measured using the quantitative real-time polymerase chain reaction, and correlation tests with disease ranking, as well as laboratory parameters, were performed. Compared with controls, TRPV2 and TRPC1 mRNA expression was lower, while that of TRPM2, was higher in PBMCs of UC and CD patients. Moreover, TRPV3 mRNA expression was lower, while that of TRPV4 was higher in CD patients. TRPC6 mRNA expression was higher in patients with CD than in patients with UC. There was also a tendency for the expression of TRPV2 mRNA to be negatively correlated with disease activity in patients with UC and CD, while that of TRPM4 mRNA was negatively correlated with disease activity only in patients with UC. PBMCs from patients with IBD exhibited varying mRNA expression levels of TRP channel members, which may play an important role in the progression of IBD.
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Özcan, SS, G. Gürel, and M. Çakır. "Gene expression profiles of transient receptor potential (TRP) channels in the peripheral blood mononuclear cells of psoriasis patients." Human & Experimental Toxicology 40, no. 8 (February 8, 2021): 1234–40. http://dx.doi.org/10.1177/0960327121991911.
Full textAbstract:
Psoriasis is a chronic autoimmune disease in which peripheral blood mononuclear cells (PBMCs) are involved in the pathological process. Transient receptor potential (TRP) channels expressed in immune cells have been shown to be associated with inflammatory diseases. We aimed to evaluate mRNA expression levels of TRP channels in PBMCs of patients with psoriasis. 30 patients with plaque psoriasis and 30 healthy age- and gender-matched control subjects were included in this study. mRNA expression levels of TRP channels in psoriasis patients were determined by Real-time polymerase chain reaction. A decreased TRPM4, TRPM7, TRPV3, TRPV4, and TRPC6 genes expression levels were found in the patient group compared to controls, respectively ( p = 0.045, p = 0.000, p = 0.000, p = 0.045, p = 0.009), whereas, an increased expression level was found in TRPM2 and TRPV1 genes in the patient group compared to controls ( p = 0.001 and p = 0.028). This is the first study showing the TRP channel mRNA expressions in PBMCs of psoriasis patients. Different expression patterns of TRP channels may have a role in pathogenesis of psoriasis.
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Chung, Kenny K. H., Peter S. Freestone, and Janusz Lipski. "Expression and functional properties of TRPM2 channels in dopaminergic neurons of the substantia nigra of the rat." Journal of Neurophysiology 106, no. 6 (December 2011): 2865–75. http://dx.doi.org/10.1152/jn.00994.2010.
Full textAbstract:
Transient receptor potential melastatin 2 (TRPM2) channels are sensitive to oxidative stress, and their activation can lead to cell death. Although these channels have been extensively studied in expression systems, their role in the brain, particularly in the substantia nigra pars compacta (SNc), remains unknown. In this study, we assessed the expression and functional properties of TRPM2 channels in rat dopaminergic SNc neurons, using acute brain slices. RT-PCR analysis revealed TRPM2 mRNA expression in the SNc region. Immunohistochemistry demonstrated expression of TRPM2 protein in tyrosine hydroxylase-positive neurons. Channel function was tested with whole cell patch-clamp recordings and calcium (fura-2) imaging. Intracellular application of ADP-ribose (50–400 μM) evoked a dose-dependent, desensitizing inward current and intracellular free calcium concentration ([Ca2+]i) rise. These responses were strongly inhibited by the nonselective TRPM2 channel blockers clotrimazole and flufenamic acid. Exogenous application of H2O2 (1–5 mM) evoked a rise in [Ca2+]i and an outward current mainly due to activation of ATP-sensitive potassium (KATP) channels. Inhibition of K+ conductance with Cs+ and tetraethylammonium unmasked an inward current. The inward current and/or [Ca2+]i rise were partially blocked by clotrimazole and N-( p-amylcinnamoyl)anthranilic acid (ACA). The H2O2-induced [Ca2+]i rise was abolished in “zero” extracellular Ca2+ concentration and was enhanced at higher baseline [Ca2+]i, consistent with activation of TRPM2 channels in the cell membrane. These results provide evidence for the functional expression of TRPM2 channels in dopaminergic SNc neurons. Given the involvement of oxidative stress in degeneration of SNc neurons in Parkinson's disease, further studies are needed to determine the pathophysiological role of these channels in the disease process.
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Tóth, Balázs, Iordan Iordanov, and László Csanády. "Ruling out pyridine dinucleotides as true TRPM2 channel activators reveals novel direct agonist ADP-ribose-2′-phosphate." Journal of General Physiology 145, no. 5 (April 27, 2015): 419–30. http://dx.doi.org/10.1085/jgp.201511377.
Full textAbstract:
Transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable cation channel implicated in postischemic neuronal cell death, leukocyte activation, and insulin secretion, is activated by intracellular ADP ribose (ADPR). In addition, the pyridine dinucleotides nicotinamide-adenine-dinucleotide (NAD), nicotinic acid–adenine-dinucleotide (NAAD), and NAAD-2′-phosphate (NAADP) have been shown to activate TRPM2, or to enhance its activation by ADPR, when dialyzed into cells. The precise subset of nucleotides that act directly on the TRPM2 protein, however, is unknown. Here, we use a heterologously expressed, affinity-purified–specific ADPR hydrolase to purify commercial preparations of pyridine dinucleotides from substantial contaminations by ADPR or ADPR-2′-phosphate (ADPRP). Direct application of purified NAD, NAAD, or NAADP to the cytosolic face of TRPM2 channels in inside-out patches demonstrated that none of them stimulates gating, or affects channel activation by ADPR, indicating that none of these dinucleotides directly binds to TRPM2. Instead, our experiments identify for the first time ADPRP as a true direct TRPM2 agonist of potential biological interest.
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Zou, Jie, Justin F. Ainscough, Wei Yang, Alicia Sedo, Shu-Ping Yu, Zhu-Zhong Mei, Asipu Sivaprasadarao, David J. Beech, and Lin-Hua Jiang. "A differential role of macrophage TRPM2 channels in Ca2+ signaling and cell death in early responses to H2O2." American Journal of Physiology-Cell Physiology 305, no. 1 (July 1, 2013): C61—C69. http://dx.doi.org/10.1152/ajpcell.00390.2012.
Full textAbstract:
Reactive oxygen species such as H2O2 elevates the cytosolic Ca2+ concentration ([Ca2+]c) and causes cell death via poly(ADPR) polymerase (PARP) activation, which also represents the primary mechanism by which H2O2 activate the transient receptor potential melastatin-related 2 (TRPM2) channel as a Ca2+-permeable channel present in the plasma membrane or an intracellular Ca2+-release channel. The present study aimed to define the contribution and mechanisms of the TRPM2 channels in macrophage cells in mediating Ca2+ signaling and cell death during initial response to H2O2, using mouse peritoneal macrophage, RAW264.7, and differentiated THP-1 cells. H2O2 evoked robust increases in the [Ca2+]c, and such Ca2+ responses were significantly greater at body temperature than room temperature. H2O2-induced Ca2+ responses were strongly inhibited by pretreatment with PJ-34, a PARP inhibitor, and largely prevented by removal of extracellular Ca2+. Furthermore, H2O2-induced increases in the [Ca2+]c were completely abolished in macrophage cells isolated from trpm2 −/− mice. H2O2 reduced macrophage cell viability in a duration- and concentration-dependent manner. H2O2-induced cell death was significantly attenuated by pretreatment with PJ-34 and TRPM2 channel deficiency but remained significant and persistent. Taken together, these results show that the TRPM2 channel in macrophage cells functions as a cell surface Ca2+-permeable channel that mediates Ca2+ influx and constitutes the principal Ca2+ signaling mechanism but has a limited, albeit significant, role in cell death during early exposure to H2O2.
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Zhang, Wenyi, Qin Tong, Kathleen Conrad, Jocelyn Wozney, Joseph Y. Cheung, and Barbara A. Miller. "Regulation of TRP channel TRPM2 by the tyrosine phosphatase PTPL1." American Journal of Physiology-Cell Physiology 292, no. 5 (May 2007): C1746—C1758. http://dx.doi.org/10.1152/ajpcell.00569.2006.
Full textAbstract:
TRPM2, a member of the transient receptor potential (TRP) superfamily, is a Ca2+-permeable channel, which mediates susceptibility to cell death following activation by oxidative stress, TNFα, or β-amyloid peptide. We determined that TRPM2 is rapidly tyrosine phosphorylated after stimulation with H2O2or TNFα. Inhibition of tyrosine phosphorylation with the tyrosine kinase inhibitors genistein or PP2 significantly reduced the increase in [Ca2+]iobserved after H2O2or TNFα treatment in TRPM2-expressing cells, suggesting that phosphorylation is important in TRPM2 activation. Utilizing a TransSignal PDZ domain array blot to identify proteins which interact with TRPM2, we identified PTPL1 as a potential binding protein. PTPL1 is a widely expressed tyrosine phosphatase, which has a role in cell survival and tumorigenesis. Immunoprecipitation and glutathione- S-transferase pull-down assays confirmed that TRPM2 and PTPL1 interact. To examine the ability of PTPL1 to modulate phosphorylation or activation of TRPM2, PTPL1 was coexpressed with TRPM2 in human embryonic kidney-293T cells. This resulted in significantly reduced TRPM2 tyrosine phosphorylation, and inhibited the rise in [Ca2+]iand the loss of cell viability, which follow H2O2or TNFα treatment. Consistent with these findings, reduction in endogenous PTPL1 expression with small interfering RNA resulted in increased TRPM2 tyrosine phosphorylation, a significantly greater rise in [Ca2+]ifollowing H2O2treatment, and enhanced susceptibility to H2O2-induced cell death. Endogenous TRPM2 and PTPL1 was associated in U937-ecoR cells, confirming the physiological relevance of this interaction. These data demonstrate that tyrosine phosphorylation of TRPM2 is important in its activation and function and that inhibition of TRPM2 tyrosine phosphorylation reduces Ca2+influx and protects cell viability. They also suggest that modulation of TRPM2 tyrosine phosphorylation is a mechanism through which PTPL1 may mediate resistance to cell death.
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An, Xinfang, Zixing Fu, Chendi Mai, Weiming Wang, Linyu Wei, Dongliang Li, Chaokun Li, and Lin-Hua Jiang. "Increasing the TRPM2 Channel Expression in Human Neuroblastoma SH-SY5Y Cells Augments the Susceptibility to ROS-Induced Cell Death." Cells 8, no. 1 (January 8, 2019): 28. http://dx.doi.org/10.3390/cells8010028.
Full textAbstract:
Human neuroblastoma SH-SY5Y cells are a widely-used human neuronal cell model in the study of neurodegeneration. A recent study shows that, 1-methyl-4-phenylpyridine ion (MPP), which selectively causes dopaminergic neuronal death leading to Parkinson’s disease-like symptoms, can reduce SH-SY5Y cell viability by inducing H2O2 generation and subsequent TRPM2 channel activation. MPP-induced cell death is enhanced by increasing the TRPM2 expression. By contrast, increasing the TRPM2 expression has also been reported to support SH-SY5Y cell survival after exposure to H2O2, leading to the suggestion of a protective role for the TRPM2 channel. To clarify the role of reactive oxygen species (ROS)-induced TRPM2 channel activation in SH-SY5Y cells, we generated a stable SH-SY5Y cell line overexpressing the human TRPM2 channel and examined cell death and cell viability after exposure to H2O2 in the wild-type and TRPM2-overexpressing SH-SY5Y cells. Exposure to H2O2 resulted in concentration-dependent cell death and reduction in cell viability in both cell types. TRPM2 overexpression remarkably augmented H2O2-induced cell death and reduction in cell viability. Furthermore, H2O2-induced cell death in both the wild-type and TRPM2-overexpressing cells was prevented by 2-APB, a TRPM2 inhibitor, and also by PJ34 and DPQ, poly(ADP-ribose) polymerase (PARP) inhibitors. Collectively, our results show that increasing the TRPM2 expression renders SH-SY5Y cells to be more susceptible to ROS-induced cell death and reinforce the notion that the TRPM2 channel plays a critical role in conferring ROS-induced cell death. It is anticipated that SH-SY5Y cells can be useful for better understanding the molecular and signaling mechanisms for ROS-induced TRPM2-mediated neurodegeneration in the pathogenesis of neurodegenerative diseases.
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Zhang, Zhiyou, Wenyi Zhang, Dae Young Jung, Hwi Jin Ko, Yongjin Lee, Randall H. Friedline, Eunjung Lee, et al. "TRPM2 Ca2+ channel regulates energy balance and glucose metabolism." American Journal of Physiology-Endocrinology and Metabolism 302, no. 7 (April 1, 2012): E807—E816. http://dx.doi.org/10.1152/ajpendo.00239.2011.
Full textAbstract:
TRPM2 Ca2+-permeable cation channel is widely expressed and activated by markers of cellular stress. Since inflammation and stress play a major role in insulin resistance, we examined the role of TRPM2 Ca2+ channel in glucose metabolism. A 2-h hyperinsulinemic euglycemic clamp was performed in TRPM2-deficient (KO) and wild-type mice to assess insulin sensitivity. To examine the effects of diet-induced obesity, mice were fed a high-fat diet for 4–10 mo, and metabolic cage and clamp studies were conducted in conscious mice. TRPM2-KO mice were more insulin sensitive partly because of increased glucose metabolism in peripheral organs. After 4 mo of high-fat feeding, TRPM2-KO mice were resistant to diet-induced obesity, and this was associated with increased energy expenditure and elevated expressions of PGC-1α, PGC-1β, PPARα, ERRα, TFAM, and MCAD in white adipose tissue. Hyperinsulinemic euglycemic clamps showed that TRPM2-KO mice were more insulin sensitive, with increased Akt and GSK-3β phosphorylation in heart. Obesity-mediated inflammation in adipose tissue and liver was attenuated in TRPM2-KO mice. Overall, TRPM2 deletion protected mice from developing diet-induced obesity and insulin resistance. Our findings identify a novel role of TRPM2 Ca2+ channel in the regulation of energy expenditure, inflammation, and insulin resistance.
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Sharma, Jyotika, Jitendra Tripathi, Atul Sharma, Christopher Ned Jondle, and Bibhuti B. Mishra. "Protective function of Calcium permeable cation channel TRPM2 during pneumoseptic Klebsiella pneumoniae infection." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 121.15. http://dx.doi.org/10.4049/jimmunol.198.supp.121.15.
Full textAbstract:
Abstract Calcium influx mediated by plasma membrane calcium permeable cation channels play essential role in immune homeostasis. Transient receptor potential melastatin 2 (Trpm2) is a trp superfamily member cationic channel which is reported to shape several effector functions of myeloid cells. Because of its role in neutrophil chemotaxis, we examined a yet undetermined function of Trpm2 in pathogenesis of Klebsiella pneumoniae (KPn), a causative agent of pneumonic sepsis with a significant neutrophil component. Here we show that Trpm2−/− mice exhibit significantly increased susceptibility to pulmonary KPn infection corresponding with an increased bacterial burden and exacerbated tissue pathology. This correlated with a modulation of local and systemic inflammatory response in-vivo in KPn infected Trpm2−/− mice as well as altered calcium influx, ROS generation and MAP kinase activity in Trpm2 deficient neutrophils compared with their WT counterparts. Our data suggest that Trpm2 regulates KPn pathogenesis by controlling neutrophil mediated inflammation and oxidative stress.
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Barth, Daniel, Andreas Lückhoff, and Frank J. P. Kühn. "Species-Specific Regulation of TRPM2 by PI(4,5)P2 via the Membrane Interfacial Cavity." International Journal of Molecular Sciences 22, no. 9 (April 28, 2021): 4637. http://dx.doi.org/10.3390/ijms22094637.
Full textAbstract:
The human apoptosis channel TRPM2 is stimulated by intracellular ADR-ribose and calcium. Recent studies show pronounced species-specific activation mechanisms. Our aim was to analyse the functional effect of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), commonly referred to as PIP2, on different TRPM2 orthologues. Moreover, we wished to identify the interaction site between TRPM2 and PIP2. We demonstrate a crucial role of PIP2, in the activation of TRPM2 orthologues of man, zebrafish, and sea anemone. Utilizing inside-out patch clamp recordings of HEK-293 cells transfected with TRPM2, differential effects of PIP2 that were dependent on the species variant became apparent. While depletion of PIP2 via polylysine uniformly caused complete inactivation of TRPM2, restoration of channel activity by artificial PIP2 differed widely. Human TRPM2 was the least sensitive species variant, making it the most susceptible one for regulation by changes in intramembranous PIP2 content. Furthermore, mutations of highly conserved positively charged amino acid residues in the membrane interfacial cavity reduced the PIP2 sensitivity in all three TRPM2 orthologues to varying degrees. We conclude that the membrane interfacial cavity acts as a uniform PIP2 binding site of TRPM2, facilitating channel activation in the presence of ADPR and Ca2+ in a species-specific manner.
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Hong, Dae Ki, A. Ra Kho, Song Hee Lee, Jeong Hyun Jeong, Beom Seok Kang, Dong Hyeon Kang, Min Kyu Park, et al. "Transient Receptor Potential Melastatin 2 (TRPM2) Inhibition by Antioxidant, N-Acetyl-l-Cysteine, Reduces Global Cerebral Ischemia-Induced Neuronal Death." International Journal of Molecular Sciences 21, no. 17 (August 21, 2020): 6026. http://dx.doi.org/10.3390/ijms21176026.
Full textAbstract:
A variety of pathogenic mechanisms, such as cytoplasmic calcium/zinc influx, reactive oxygen species production, and ionic imbalance, have been suggested to play a role in cerebral ischemia induced neurodegeneration. During the ischemic state that occurs after stroke or heart attack, it is observed that vesicular zinc can be released into the synaptic cleft, and then translocated into the cytoplasm via various cation channels. Transient receptor potential melastatin 2 (TRPM2) is highly distributed in the central nervous system and has high sensitivity to oxidative damage. Several previous studies have shown that TRPM2 channel activation contributes to neuroinflammation and neurodegeneration cascades. Therefore, we examined whether anti-oxidant treatment, such as with N-acetyl-l-cysteine (NAC), provides neuroprotection via regulation of TRPM2, following global cerebral ischemia (GCI). Experimental animals were then immediately injected with NAC (150 mg/kg/day) for 3 and 7 days, before sacrifice. We demonstrated that NAC administration reduced activation of GCI-induced neuronal death cascades, such as lipid peroxidation, microglia and astroglia activation, free zinc accumulation, and TRPM2 over-activation. Therefore, modulation of the TRPM2 channel can be a potential therapeutic target to prevent ischemia-induced neuronal death.
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Evtushenko, Anna A., Irina P. Voronova, and Tamara V. Kozyreva. "Effect of Long-Term Adaptation to Cold and Short-Term Cooling on the Expression of the TRPM2 Ion Channel Gene in the Hypothalamus of Rats." Current Issues in Molecular Biology 45, no. 2 (January 20, 2023): 1002–11. http://dx.doi.org/10.3390/cimb45020065.
Full textAbstract:
The present study is aimed to elucidate the possible involvement of the thermosensitive TRPM2 ion channel in changing of the temperature sensitivity of the hypothalamus after different cold exposures—long-term adaptation to cold and short-term cooling. Quantitative RT-PCR was used to study the expression of the gene of thermosensitive TRPM2 ion channel in the hypothalamus in the groups of control (kept for 5 weeks at +20 to +22 °C) and cold-adapted (5 weeks at +4 to +6 °C) rats, as well as in the groups of animals which were subjected to acute cooling (rapid or slow) with subsequent restoration of body temperature to the initial level. It has been shown that after long-term adaptation to cold, the decrease in the Trpm2 gene expression was observed in the hypothalamus, while a short-term cooling does not affect the expression of the gene of this ion channel. Thus, long-term adaptation to cold results in the decrease in the activity not only of the TRPV3 ion channel gene, as shown earlier, but also of the Trpm2 gene in the hypothalamus. The overlapping temperature ranges of the functioning of these ion channels and their unidirectional changes during the adaptation of the homoeothermic organism to cold suggest their functional interaction. The decrease in the Trpm2 gene expression may indicate the participation of this ion channel in adaptive changes in hypothalamic thermosensitivity, but only as a result of long-term cold exposure and not of a short-term cooling. These processes occurring at the genomic level are one of the molecular mechanisms of the adaptive changes.
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Du, Jianyang, Jia Xie, and Lixia Yue. "Intracellular calcium activates TRPM2 and its alternative spliced isoforms." Proceedings of the National Academy of Sciences 106, no. 17 (April 16, 2009): 7239–44. http://dx.doi.org/10.1073/pnas.0811725106.
Full textAbstract:
Melastatin-related transient receptor potential channel 2 (TRPM2) is a Ca2+-permeable, nonselective cation channel that is involved in oxidative stress-induced cell death and inflammation processes. Although TRPM2 can be activated by ADP-ribose (ADPR) in vitro, it was unknown how TRPM2 is gated in vivo. Moreover, several alternative spliced isoforms of TRPM2 identified recently are insensitive to ADPR, and their gating mechanisms remain unclear. Here, we report that intracellular Ca2+ ([Ca2+]i) can activate TRPM2 as well as its spliced isoforms. We demonstrate that TRPM2 mutants with disrupted ADPR-binding sites can be activated readily by [Ca2+]i, indicating that [Ca2+]i gating of TRPM2 is independent of ADPR. The mechanism by which [Ca2+]i activates TRPM2 is via a calmodulin (CaM)-binding domain in the N terminus of TRPM2. Whereas Ca2+-mediated TRPM2 activation is independent of ADPR and ADPR-binding sites, both [Ca2+]i and the CaM-binding motif are required for ADPR-mediated TRPM2 gating. Importantly, we demonstrate that intracellular Ca2+ release activates both recombinant and endogenous TRPM2 in intact cells. Moreover, receptor activation-induced Ca2+ release is capable of activating TRPM2. These results indicate that [Ca2+]i is a key activator of TRPM2 and the only known activator of the spliced isoforms of TRPM2. Our findings suggest that [Ca2+]i-mediated activation of TRPM2 and its alternative spliced isoforms may represent a major gating mechanism in vivo, therefore conferring important physiological and pathological functions of TRPM2 and its spliced isoforms in response to elevation of [Ca2+]i.
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Wang, Jing, Michael F. Jackson, and Yu-Feng Xie. "Glia and TRPM2 Channels in Plasticity of Central Nervous System and Alzheimer’s Diseases." Neural Plasticity 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/1680905.
Full textAbstract:
Synaptic plasticity refers to the ability of neurons to strengthen or weaken synaptic efficacy in response to activity and is the basis for learning and memory. Glial cells communicate with neurons and in this way contribute in part to plasticity in the CNS and to the pathology of Alzheimer’s disease (AD), a neurodegenerative disease in which impaired synaptic plasticity is causally implicated. The transient receptor potential melastatin member 2 (TRPM2) channel is a nonselective Ca2+-permeable channel expressed in both glial cells (microglia and astrocytes) and neurons. Recent studies indicated that TRPM2 regulates synaptic plasticity as well as the activation of glial cells. TRPM2 also modulates oxidative stress and inflammation through interaction with glial cells. As both oxidative stress and inflammation have been implicated in AD pathology, this suggests a possible contribution of TRPM2 to disease processes. Through modulating the homeostasis of glutathione, TRPM2 is involved in the process of aging which is a risk factor of AD. These results potentially point TRPM2 channel to be involved in AD through glial cells. This review summarizes recent advances in studying the contribution of TRPM2 in health and in AD pathology, with a focus on contributions via glia cells.
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Sumoza-Toledo, Adriana, Ingo Lange, Harivadan Bhagat, Hanna Cortado, Yasuo Mori, Reinhold Penner, Santiago Partida-Sanchez, and Andrea Fleig. "Transient Receptor Potential Melastatin 2 (TRPM2) is a Calcium Release Channel Essential for Chemotaxis of Dendritic Cells (44.17)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 44.17. http://dx.doi.org/10.4049/jimmunol.184.supp.44.17.
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Abstract Chemokines induce Ca2+ signaling and chemotaxis in dendritic cells (DCs) but the molecular players involved in shaping the changes in intracellular Ca2+ remain to be characterized. Using siRNA and knock-out mice, we show that in addition to IP3-mediated Ca2+ release and store-operated Ca2+ entry the transient receptor potential melastatin 2 (TRPM2) channel contributes to Ca2+ release, but not Ca2+ influx in mouse DCs. Consistent with this observation, TRPM2 expression in DCs cells is restricted to endolysosomal vesicles, whereas in neutrophils the channel localizes to the plasma membrane and does not participate in Ca2+ release. While TRPM2 is not involved in DCs maturation, TRPM2-deficient DCs show severely compromised chemotaxis regardless of maturation stage. This is due to perturbed Ca2+ signaling manifested through suppression of specific TRPM2-mediated Ca2+-release events and an additional secondary modification of store-operated Ca2+ entry. DCs deficient in both TRPM2 and inositol-1,4,5-trisphosphate receptor signaling (InsP3R) lose their ability to perform chemotaxis entirely. These findings confirm ADPR as a novel second messenger and highlight TRPM2 as a key player regulating DCs chemotaxis through its function as Ca2+ release channel.
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Steinman, Joe, Andrea Ovcjak, Zhengwei Luo, Xinyang Zhang, Luiz Roberto Britto, Jeffrey T. Henderson, Hong-Shuo Sun, and Zhong-Ping Feng. "Transient receptor potential melastatin 2 channels in neurological disorders: Mechanisms and animal models." Advanced Neurology 1, no. 1 (April 8, 2022): 1–18. http://dx.doi.org/10.36922/an.v1i1.3.
Full textAbstract:
Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable ion channel implicated in neurodegenerative disorders and conditions. It is activated in response to reactive oxygen species (ROS) and thereby alters Ca2+ homeostasis and initiates pathways that lead to apoptosis and cell dysfunction. This review summarizes the current role of TRPM2 in neurological disorders, including Parkinson’s disease, Alzheimer’s disease, ischemia, traumatic brain injury, and depressive disorders (bipolar disease and depression). It describes the distribution and function of the TRPM2 channel across the brain and highlights common mechanisms between diseases. Specific animal and cell culture studies using TRPM2 inhibitors or genetic knockouts are discussed, including strategies to reduce the effect of ROS in disease through TRPM2 inhibition.
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Zhang, Wenyi, Iwona Hirschler-Laszkiewicz, Qin Tong, Kathleen Conrad, Shao-Cong Sun, Linda Penn, Dwayne L. Barber, et al. "TRPM2 is an ion channel that modulates hematopoietic cell death through activation of caspases and PARP cleavage." American Journal of Physiology-Cell Physiology 290, no. 4 (April 2006): C1146—C1159. http://dx.doi.org/10.1152/ajpcell.00205.2005.
Full textAbstract:
TRPM2 is a Ca2+-permeable channel activated by oxidative stress or TNF-α, and TRPM2 activation confers susceptibility to cell death. The mechanisms were examined here in human monocytic U937-ecoR cells. This cell line expresses full-length TRPM2 (TRPM2-L) and several isoforms including a short splice variant lacking the Ca2+-permeable pore region (TRPM2-S), which functions as a dominant negative. Treatment with H2O2, a model of oxidative stress, or TNF-α results in reduced cell viability. Expression of TRPM2-L and TRPM2-S was modulated by retroviral infection. U937-ecoR cells expressing increased levels of TRPM2-L were treated with H2O2or TNF-α, and these cells exhibited significantly increased intracellular calcium concentration ([Ca2+]i), decreased viability, and increased apoptosis. A dramatic increase in cleavage of caspases-8, -9, -3, and -7 and poly(ADP-ribose)polymerase (PARP) was observed, demonstrating a downstream mechanism through which cell death is mediated. Bcl-2 levels were unchanged. Inhibition of the [Ca2+]irise with the intracellular Ca2+chelator BAPTA blocked caspase/PARP cleavage and cell death induced after activation of TRPM2-L, demonstrating the critical role of [Ca2+]iin mediating these effects. Downregulation of endogenous TRPM2 by RNA interference or increased expression of TRPM2-S inhibited the rise in [Ca2+]i, enhanced cell viability, and reduced numbers of apoptotic cells after exposure to oxidative stress or TNF-α, demonstrating the physiological importance of TRPM2. Our data show that one mechanism through which oxidative stress or TNF-α mediates cell death is activation of TRPM2, resulting in increased [Ca2+]i, followed by caspase activation and PARP cleavage. Inhibition of TRPM2-L function by reduction in TRPM2 levels, interaction with TRPM2-S, or Ca2+chelation antagonizes this important cell death pathway.
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Li, Yuan, Heather Knowth, Justin Heizer, Jenny Mogan, and Anne-Laure Perraud. "The TRPM2 ion channel is required for early innate immunity against Listeria infection (110.20)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 110.20. http://dx.doi.org/10.4049/jimmunol.186.supp.110.20.
Full textAbstract:
Abstract TRPM2 is a non-selective cationic channel, which can mediate Ca2+ fluxes in response to H2O2, indicating a role in signaling as a sensor of oxidative stress. TRPM2 is functionally expressed in many immune cell types, and has been reported to be required for neutrophil chemotaxis and production of the chemokine CXCL2. In order to investigate the function of TRPM2 in response to a pathogen, we infected TRPM2-/- mice with Listeria monocytogenes (Lm). We found that TRPM2-/- mice show higher mortality and strongly elevated bacterial burdens already at an early stage of Lm infection. This susceptibility to Lm infection is not caused by defects in the recruitment of neutrophils, as neutrophil migration remains intact in Lm-infected TRPM2-/- mice. Because the production of IFNγ and IL-12 is reduced in TRPM2-/- mice, we conclude that TRPM2 can enhance the production of some cytokines. Bone marrow transfer experiments suggest that the susceptibility of TRPM2-/- mice to Lm infection might originate from both immune cells and nonhematopoietic cells. In sum, we have demonstrated the importance of TRPM2 in enhancing the crucial production of cytokines during early immunity against Lm.
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Hermosura, Meredith C., Aaron M. Cui, Ramon Christopher V. Go, Bennett Davenport, Cory M. Shetler, Justin W. Heizer, Carsten Schmitz, Gabor Mocz, Ralph M. Garruto, and Anne-Laure Perraud. "Altered functional properties of a TRPM2 variant in Guamanian ALS and PD." Proceedings of the National Academy of Sciences 105, no. 46 (November 12, 2008): 18029–34. http://dx.doi.org/10.1073/pnas.0808218105.
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Two related neurodegenerative disorders, Western Pacific amyotrophic lateral sclerosis (ALS) and parkinsonism–dementia (PD), originally occurred at a high incidence on Guam, in the Kii peninsula of Japan, and in southern West New Guinea more than 50 years ago. These three foci shared a unique mineral environment characterized by the presence of severely low levels of Ca2+ and Mg2+, coupled with high levels of bioavailable transition metals in the soil and drinking water. Epidemiological studies suggest that genetic factors also contribute to the etiology of these disorders. Here, we report that a variant of the transient receptor potential melastatin 2 (TRPM2) gene may confer susceptibility to these diseases. TRPM2 encodes a calcium-permeable cation channel highly expressed in the brain that has been implicated in mediating cell death induced by oxidants. We found a heterozygous variant of TRPM2 in a subset of Guamanian ALS (ALS-G) and PD (PD-G) cases. This variant, TRPM2P1018L, produces a missense change in the channel protein whereby proline 1018 (Pro1018) is replaced by leucine (Leu1018). Functional studies revealed that, unlike WT TRPM2, P1018L channels inactivate. Our results suggest that the ability of TRPM2 to maintain sustained ion influx is a physiologically important function and that its disruption may, under certain conditions, contribute to disease states.
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Algood, Holly Marie Scott, Beverly R. E. A. Dixon, Danyvid Olivares-Villagomez, Carlos Henrique Serezani, M. Kay Washington, Jeffrey C. Rathmell, and Lori A. Coburn. "The impact of the TRPM2 ion channel on inflammation and macrophage metabolism in gastrointestinal models." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 117.20. http://dx.doi.org/10.4049/jimmunol.202.supp.117.20.
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Abstract Macrophages can play a vital role in regulating pro-inflammatory pathways that drive chronic inflammation and impact carcinogenesis. We previously published that TRPM2 regulates ROS production and the pro-inflammatory cytokine profile of macrophages in vivo and in vitro in H. pylori infection models. Since macrophage function and activation profiles can be regulated by metabolism, the impact of the TRPM2 channel on macrophage metabolism was assessed using bone marrow derived macrophages in Seahorse Extracellular Flux Assays and Mitotracker assays. The data demonstrated an unfavorable shift in mitochondrial content in Trpm2−/− macrophages after M1 activation. Consistent with this shift, the oxygen consumption rate was reduced in Trpm2−/− macrophages compared to WT macrophages, and the extracellular acidification rate at baseline and glycolytic reserve were higher in Trpm2−/− macrophages following classical activation. To investigate the role of TRPM2 in controlling other gastrointestinal pathologies, including acute colitis and carcinogenesis, the dextran sulfate sodium (DSS) colitis model and the azoxymethane (AOM)/DSS colitis-associated cancer (CAC) model were used. Trpm2−/− mice were not protected against acute DSS-induced colitis. Our endpoint analysis in the CAC model demonstrated that Trpm2−/− mice developed more numerous but smaller tumors than WT mice and immunohistological analysis suggests a shift in numbers of innate cells in the Trpm2−/− tumors compared to WT tumors. In the non-tumor areas, the histological injury score was reduced in the Trpm2−/− mice compared to WT mice. These data suggest that TRPM2 regulates Mϕ metabolism and impacts inflammation in the gastrointestinal tract.
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Starkus, John, Andreas Beck, Andrea Fleig, and Reinhold Penner. "Regulation of TRPM2 by Extra- and Intracellular Calcium." Journal of General Physiology 130, no. 4 (September 24, 2007): 427–40. http://dx.doi.org/10.1085/jgp.200709836.
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TRPM2 is a calcium-permeable nonselective cation channel that is opened by the binding of ADP-ribose (ADPR) to a C-terminal nudix domain. Channel activity is further regulated by several cytosolic factors, including cyclic ADPR (cADPR), nicotinamide adenine dinucleotide phosphate (NAADP), Ca2+ and calmodulin (CaM), and adenosine monophosphate (AMP). In addition, intracellular ions typically used in patch-clamp experiments such as Cs+ or Na+ can alter ADPR sensitivity and voltage dependence, complicating the evaluation of the roles of the various modulators in a physiological context. We investigated the roles of extra- and intracellular Ca2+ as well as CaM as modulators of ADPR-induced TRPM2 currents under more physiological conditions, using K+-based internal saline in patch-clamp experiments performed on human TRPM2 expressed in HEK293 cells. Our results show that in the absence of Ca2+, both internally and externally, ADPR alone cannot induce cation currents. In the absence of extracellular Ca2+, a minimum of 30 nM internal Ca2+ is required to cause partial TRPM2 activation with ADPR. However, 200 μM external Ca2+ is as efficient as 1 mM Ca2+ in TRPM2 activation, indicating an external Ca2+ binding site important for proper channel function. Ca2+ facilitates ADPR gating with a half-maximal effective concentration of 50 nM and this is independent of extracellular Ca2+. Furthermore, TRPM2 currents inactivate if intracellular Ca2+ levels fall below 100 nM irrespective of extracellular Ca2+. The facilitatory effect of intracellular Ca2+ is not mimicked by Mg2+, Ba2+, or Zn2+. Only Sr2+ facilitates TRPM2 as effectively as Ca2+, but this is due to Sr2+-induced Ca2+ release from internal stores rather than a direct effect of Sr2+ itself. Together, these data demonstrate that cytosolic Ca2+ regulates TRPM2 channel activation. Its facilitatory action likely occurs via CaM, since the addition of 100 μM CaM to the patch pipette significantly enhances ADPR-induced TRPM2 currents at fixed [Ca2+]i and this can be counteracted by calmidazolium. We conclude that ADPR is responsible for TRPM2 gating and Ca2+ facilitates activation via calmodulin.
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Scharenberg, Andrew M. "TRPM2 and TRPM7: channel/enzyme fusions to generate novel intracellular sensors." Pflügers Archiv - European Journal of Physiology 451, no. 1 (July 7, 2005): 220–27. http://dx.doi.org/10.1007/s00424-005-1444-0.
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Klumpp, Dominik, Milan Misovic, Kalina Szteyn, Ekaterina Shumilina, Justine Rudner, and Stephan M. Huber. "Targeting TRPM2 Channels Impairs Radiation-Induced Cell Cycle Arrest and Fosters Cell Death of T Cell Leukemia Cells in a Bcl-2-Dependent Manner." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–14. http://dx.doi.org/10.1155/2016/8026702.
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Messenger RNA data of lymphohematopoietic cancer lines suggest a correlation between expression of the cation channel TRPM2 and the antiapoptotic protein Bcl-2. The latter is overexpressed in various tumor entities and mediates therapy resistance. Here, we analyzed the crosstalk between Bcl-2 and TRPM2 channels in T cell leukemia cells during oxidative stress as conferred by ionizing radiation (IR). To this end, the effects of TRPM2 inhibition or knock-down on plasma membrane currents, Ca2+signaling, mitochondrial superoxide anion formation, and cell cycle progression were compared between irradiated (0–10 Gy) Bcl-2-overexpressing and empty vector-transfected Jurkat cells. As a result, IR stimulated a TRPM2-mediated Ca2+-entry, which was higher in Bcl-2-overexpressing than in control cells and which contributed to IR-induced G2/M cell cycle arrest. TRPM2 inhibition induced a release from G2/M arrest resulting in cell death. Collectively, this data suggests a pivotal function of TRPM2 in the DNA damage response of T cell leukemia cells. Apoptosis-resistant Bcl-2-overexpressing cells even can afford higher TRPM2 activity without risking a hazardous Ca2+-overload-induced mitochondrial superoxide anion formation.
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ABSTRACT BOOK, Anonymes. "Abstract Book of 7th Brain Research School (2022-BRS), 27 June and 3 July 2022, Isparta, Turkey (http://2022.brs.org.tr/)." Journal of Cellular Neuroscience and Oxidative Stress 14, no. 2 (Supplement 1) (July 14, 2022): 1–24. http://dx.doi.org/10.37212/jcnos.1143834.
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7th Brain Research School (2022-BRS) was performed in Isparta, Turkey between 27 June and 3 July 2022 (http://2022.brs.org.tr/). There were abstracts of 8 speakers, 11 oral presentations, and 3 poster presentations in the 2022-BRS. Titles of speakers; 1- Mustafa NAZIROĞLU. Fluorescent Ca2+ stains for imaging the mice microglia. 2- Beatrice Mihaela RADU. Low-energy accelerated protons irradiation inhibits DNA repair and diminishes cell proliferation, migration and calcium signaling in brain microvascular endothelial cells. 3- Nashat ABUMARIA. Behavioral assays and animal models of psychiatric disorders. 4- Ferah YILDIRIM. Mapping genome-wide DNA methylation changes in alcohol use disorder (No abstrcat). 5- Marco CANEPARI. Principles of Ca2+ imaging using low-affinity indicators. 6- Denis ROUSSEAU. Western blot analyses in the mitochondria. 7- Xinhua SHU. Protection of p-Coumaric acid against depression and memory impairment via inhibition of neuroinflammation 8- Simon HEBEISEN. State dependent block of voltage gated sodium and calcium channels as modern treatment for epilepsy. Titles of oral presentations (OPs); OP1. Bünyamin AYDIN. Diabetic neuropathic pain and TRPM2 Channel: Focus on selenium. OP2. Agomelatine attenuates calcium signaling and apoptosis via the inhibition of TRPV1 channel in the hippocampal neurons of rats with chronic mild stress depression model. OP3. Hatice DALDAL. An interaction between cisplatin-induced optic nerve injury and TRPM2 channel. OP4. Kemal ERTİLAV. Recent developments on the traumatic brain injury models in the experimental animals. OP5. Kaan ERBAKAN. Involvement of TRPV1 channel in the etiology of epilepsy. OP6. Ramazan ÇINAR. Does GSH depletion induce TRPM2 activation in neuronal cells? OP7. Esin AKBAY ÇETİN. TRP ion channels and approaches in COVID-19. OP8. Gülin ÖZDAMAR ÜNAL. Early life stress and neuroinflammation. OP9. Adem AHLATCI. Investigation of TRPM2 cation channel activation in PTZ-induced SH-SY5Y cells by patch-clamp technique: Regulatory role of valproic acid. OP10. Yener YAZĞAN. Orthodontic teeth movement-induced pain and TRPV1 channel. OP11. Evaluation of the role of Radish (Raphanus sativus) extract in movement tests in MPTP induced experimental Parkinson's model in Balb/C mice. Titles of poster presentations (P); P1- Esin AKBAY ÇETİN. Probable pathways of SARS-CoV-2 to central nervous system. P2. Yusuf DAL. Low molecular weight heparin treatment reduced apoptosis, oxidative stress, and calcium signaling in the thrombocytes of patients with recurrent pregnancy loss and thrombophilia: Involvements of TRPM2 and TRPV1 channels. P3. Ferruh KARAMANGİL. Investigation of frequency and diversity of experimental animal models of schizophrenia.
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Ali, Eunus S., Grigori Y. Rychkov, and Greg J. Barritt. "TRPM2 Non-Selective Cation Channels in Liver Injury Mediated by Reactive Oxygen Species." Antioxidants 10, no. 8 (August 3, 2021): 1243. http://dx.doi.org/10.3390/antiox10081243.
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TRPM2 channels admit Ca2+ and Na+ across the plasma membrane and release Ca2+ and Zn2+ from lysosomes. Channel activation is initiated by reactive oxygen species (ROS), leading to a subsequent increase in ADP-ribose and the binding of ADP-ribose to an allosteric site in the cytosolic NUDT9 homology domain. In many animal cell types, Ca2+ entry via TRPM2 channels mediates ROS-initiated cell injury and death. The aim of this review is to summarise the current knowledge of the roles of TRPM2 and Ca2+ in the initiation and progression of chronic liver diseases and acute liver injury. Studies to date provide evidence that TRPM2-mediated Ca2+ entry contributes to drug-induced liver toxicity, ischemia–reperfusion injury, and the progression of non-alcoholic fatty liver disease to cirrhosis, fibrosis, and hepatocellular carcinoma. Of particular current interest are the steps involved in the activation of TRPM2 in hepatocytes following an increase in ROS, the downstream pathways activated by the resultant increase in intracellular Ca2+, and the chronology of these events. An apparent contradiction exists between these roles of TRPM2 and the role identified for ROS-activated TRPM2 in heart muscle and in some other cell types in promoting Ca2+-activated mitochondrial ATP synthesis and cell survival. Inhibition of TRPM2 by curcumin and other “natural” compounds offers an attractive strategy for inhibiting ROS-induced liver cell injury. In conclusion, while it has been established that ROS-initiated activation of TRPM2 contributes to both acute and chronic liver injury, considerable further research is needed to elucidate the mechanisms involved, and the conditions under which pharmacological inhibition of TRPM2 can be an effective clinical strategy to reduce ROS-initiated liver injury.
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Fliegert, Ralf, Joanna M. Watt, Anja Schöbel, Monika D. Rozewitz, Christelle Moreau, Tanja Kirchberger, Mark P. Thomas, et al. "Ligand-induced activation of human TRPM2 requires the terminal ribose of ADPR and involves Arg1433 and Tyr1349." Biochemical Journal 474, no. 13 (June 16, 2017): 2159–75. http://dx.doi.org/10.1042/bcj20170091.
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TRPM2 (transient receptor potential channel, subfamily melastatin, member 2) is a Ca2+-permeable non-selective cation channel activated by the binding of adenosine 5′-diphosphoribose (ADPR) to its cytoplasmic NUDT9H domain (NUDT9 homology domain). Activation of TRPM2 by ADPR downstream of oxidative stress has been implicated in the pathogenesis of many human diseases, rendering TRPM2 an attractive novel target for pharmacological intervention. However, the structural basis underlying this activation is largely unknown. Since ADP (adenosine 5′-diphosphate) alone did not activate or antagonize the channel, we used a chemical biology approach employing synthetic analogues to focus on the role of the ADPR terminal ribose. All novel ADPR derivatives modified in the terminal ribose, including that with the seemingly minor change of methylating the anomeric-OH, abolished agonist activity at TRPM2. Antagonist activity improved as the terminal substituent increasingly resembled the natural ribose, indicating that gating by ADPR might require specific interactions between hydroxyl groups of the terminal ribose and the NUDT9H domain. By mutating amino acid residues of the NUDT9H domain, predicted by modelling and docking to interact with the terminal ribose, we demonstrate that abrogating hydrogen bonding of the amino acids Arg1433 and Tyr1349 interferes with activation of the channel by ADPR. Taken together, using the complementary experimental approaches of chemical modification of the ligand and site-directed mutagenesis of TRPM2, we demonstrate that channel activation critically depends on hydrogen bonding of Arg1433 and Tyr1349 with the terminal ribose. Our findings allow for a more rational design of novel TRPM2 antagonists that may ultimately lead to compounds of therapeutic potential.
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Hirschler-Laszkiewicz, Iwona, Shu-jen Chen, Lei Bao, JuFang Wang, Xue-Qian Zhang, Santhanam Shanmughapriya, Kerry Keefer, Muniswamy Madesh, Joseph Y. Cheung, and Barbara A. Miller. "The human ion channel TRPM2 modulates neuroblastoma cell survival and mitochondrial function through Pyk2, CREB, and MCU activation." American Journal of Physiology-Cell Physiology 315, no. 4 (October 1, 2018): C571—C586. http://dx.doi.org/10.1152/ajpcell.00098.2018.
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Transient receptor potential melastatin channel subfamily member 2 (TRPM2) has an essential function in cell survival and is highly expressed in many cancers. Inhibition of TRPM2 in neuroblastoma by depletion with CRISPR technology or expression of dominant negative TRPM2-S has been shown to significantly reduce cell viability. Here, the role of proline-rich tyrosine kinase 2 (Pyk2) in TRPM2 modulation of neuroblastoma viability was explored. In TRPM2-depleted cells, phosphorylation and expression of Pyk2 and cAMP-responsive element-binding protein (CREB), a downstream target, were significantly reduced after application of the chemotherapeutic agent doxorubicin. Overexpression of wild-type Pyk2 rescued cell viability. Reduction of Pyk2 expression with shRNA decreased cell viability and CREB phosphorylation and expression, demonstrating Pyk2 modulates CREB activation. TRPM2 depletion impaired phosphorylation of Src, an activator of Pyk2, and this may be a mechanism to reduce Pyk2 phosphorylation. TRPM2 inhibition was previously demonstrated to decrease mitochondrial function. Here, CREB, Pyk2, and phosphorylated Src were reduced in mitochondria of TRPM2-depleted cells, consistent with their role in modulating expression and activation of mitochondrial proteins. Phosphorylated Src and phosphorylated and total CREB were reduced in TRPM2-depleted nuclei. Expression and function of mitochondrial calcium uniporter (MCU), a target of phosphorylated Pyk2 and CREB, were significantly reduced. Wild-type TRPM2 but not Ca2+-impermeable mutant E960D reconstituted phosphorylation and expression of Pyk2 and CREB in TRPM2-depleted cells exposed to doxorubicin. Results demonstrate that TRPM2 expression protects the viability of neuroblastoma through Src, Pyk2, CREB, and MCU activation, which play key roles in maintaining mitochondrial function and cellular bioenergetics.
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Partida-Sanchez, Santiago, Adriana Sumoza-Toledo, Harivadan Bhagat, Ingo Lange, Hanna Cortado, and Andrea Fleig. "Azole derivative drugs inhibit neutrophil chemotaxis by blocking the Calcium permeant channel TRPM2 (140.12)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 140.12. http://dx.doi.org/10.4049/jimmunol.184.supp.140.12.
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Abstract Azole derivatives exert direct anti-inflammatory activity in fungal infections and other cutaneous inflammatory conditions. Inhibition of PMN chemotaxis and leukotriene biosynthesis has been suggested to explain this phenomenon, yet the molecular mechanism of action for these drugs remains unknown. Recently we showed that NAD+ derived metabolites, cADPR and ADPR; regulate PMN chemotaxis by inducing extracellular Ca2+ influx via the ion channel TRPM2. Here we investigated whether azole derivatives inhibit PMN chemotaxis in vitro by altering the production of NAD+-derived metabolites or by blocking plasma membrane channel-conducted Ca2+ influx. First, we demonstrated that econazole and clotrimazole significantly inhibited PMN directionality and speed in an EZ-Taxiscan chemotaxis assay. Interestingly, econazole and clotrimazole, as well as FA, another compound proposed to block the TRPM2 channel, blocked fMLP-induced Ca2+ influx, rendering defective Ca2+ responses comparable to those responses observed in fMLP-stimulated TRPM2 KO PMN. Moreover, we found that pre-treatment of neutrophils with econazole or clotrimazole did not alter NAD+ metabolism, but its effect was by blocking a membrane channel with physiological properties similar to TRPM2. Collectively, these data suggest that compounds, which antagonize TRPM2-mediated Ca2+ signaling pathway, may function as effective inhibitors of PMN recruitment, and will likely prove useful in the treatment of inflammatory diseases.
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Robledo-Avila, Frank Hanz, Juan de Dios Ruiz Rosado, Kenneth L. Brockman, and Santiago Partida-Sanchez. "The TRPM2 ion channel regulates the inflammatory response of neutrophils during Listeria monocytogenes infection." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 148.23. http://dx.doi.org/10.4049/jimmunol.204.supp.148.23.
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Abstract Calcium signaling is required for most antimicrobial functions of neutrophils. The transient receptor potential melastatin-2 (TRPM2) cation channel has been proposed to play important roles in modulating calcium mobilization, cell migration and oxidative stress in neutrophils. However, the precise mechanism by which TRPM2 activation may exert a pro- or anti-inflammatory function remains unclear. In this study, we used a mouse model of Listeria monocytogenes infection to define the role of TRPM2 in the regulation of neutrophils’ function. We found that infected Trpm2−/− mice were associated with high bacterial burden in spleen and liver indicating increased susceptibility to Listeria infection. Pronounced migration rates of neutrophils and monocytes to the liver and spleen characterized the inflammatory response to Listeria during the first 18h. In the Trpm2−/− mice, the acute phase infection resulted in septic shock, defined by increased serum levels of TNF-α, IL-6, and IL-10, but no decreased levels of IFN-γ or IL-12. Furthermore, depletion of neutrophils demonstrated the critical role of these cells in regulating acute inflammation by conferring resistance of Trpm2−/− mice to Listeria infection. Gene expression and inflammatory cytokine analyses of infected tissues further confirmed the hyperinflammatory profile of Trpm2−/− neutrophils. Finally, the increased inflammatory properties of Trpm2−/− neutrophils correlated with cellular calcium overloading and potentiated membrane depolarization, in response to Listeria infection. In conclusion, our findings suggest that TRPM2 channel plays critical roles in the regulation of the inflammatory properties of neutrophils during Listeria monocytogenes infection.
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Riekehr, Winnie Maria, Simon Sander, Jelena Pick, Henning Tidow, Andreas Bauche, Andreas H. Guse, and Ralf Fliegert. "cADPR Does Not Activate TRPM2." International Journal of Molecular Sciences 23, no. 6 (March 15, 2022): 3163. http://dx.doi.org/10.3390/ijms23063163.
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cADPR is a second messenger that releases Ca2+ from intracellular stores via the ryanodine receptor. Over more than 15 years, it has been controversially discussed whether cADPR also contributes to the activation of the nucleotide-gated cation channel TRPM2. While some groups have observed activation of TRPM2 by cADPR alone or in synergy with ADPR, sometimes only at 37 °C, others have argued that this is due to the contamination of cADPR by ADPR. The identification of a novel nucleotide-binding site in the N-terminus of TRPM2 that binds ADPR in a horseshoe-like conformation resembling cADPR as well as the cADPR antagonist 8-Br-cADPR, and another report that demonstrates activation of TRPM2 by binding of cADPR to the NUDT9H domain raised the question again and led us to revisit the topic. Here we show that (i) the N-terminal MHR1/2 domain and the C-terminal NUDT9H domain are required for activation of human TRPM2 by ADPR and 2′-deoxy-ADPR (2dADPR), (ii) that pure cADPR does not activate TRPM2 under a variety of conditions that have previously been shown to result in channel activation, (iii) the cADPR antagonist 8-Br-cADPR also inhibits activation of TRPM2 by ADPR, and (iv) cADPR does not bind to the MHR1/2 domain of TRPM2 while ADPR does.
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Wang, Xingbang, Yong Xiao, Mingming Huang, Bing Shen, Haowei Xue, and Kaile Wu. "Effect of TRPM2-Mediated Calcium Signaling on Cell Proliferation and Apoptosis in Esophageal Squamous Cell Carcinoma." Technology in Cancer Research & Treatment 20 (January 2021): 153303382110452. http://dx.doi.org/10.1177/15330338211045213.
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Esophageal squamous cell carcinoma (ESCC) is the sixth leading cause of death due to cancer, indicating that finding new therapeutic targets or approaches for ESCC treatment is imperative. Transient Receptor Potential cation channel subfamily M, member 2 (TRPM2) is a calcium-permeable, nonselective cation channel that responds to reactive oxygen species (ROS), which are found in the tumor microenvironment and are important regulators of tumorigenesis, cell proliferation, apoptosis, and the therapeutic response. Here, we used immunohistochemical analysis of tumor tissue derived from patients with ESCC to find that the TRPM2 channel protein expression level was increased in tumor tissue compared with adjacent normal tissue. Intracellular calcium concentration measurements, western blotting, and ROS and cell viability assays were used with a human ESCC cell line (TE-1 cells) to find that TRPM2 participated in the ROS hydrogen peroxide-induced increase in intracellular calcium. This increased calcium inhibited cell proliferation and enhanced apoptosis. Pretreatment of cells with the anticancer agent 5-fluorouracil (5-FU) significantly increased ROS production, which potentiated TRPM2-mediated calcium signaling, decreased cell proliferation, and increased apoptosis in TE-1 cells, suggesting that the therapeutic effect of 5-FU in ESCC cells may be mediated by the TRPM2 channel-mediated calcium influx. These findings offer a potential treatment target and provide mechanistic insight into the therapeutic effects of 5-FU in patients with ESCC.