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1
Li, Xin. "TRPM2 channel-mediated signalling mechanisms for neuronal cell death." Thesis, University of Leeds, 2017. http://etheses.whiterose.ac.uk/18576/.
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Transient receptor potential melastatin-related 2 (TRPM2) channel is gated by ADP-ribose (ADPR) and potently activated by reactive oxygen species (ROS) through stimulating ADPR-generating mechanisms. Recent studies provide evidence to show a crucial role for TRPM2 in neuronal death and cognitive impairment associated with ischemic stroke and Alzheimer’s disease. However, the underlying mechanisms are poorly understood. Studies described in this thesis adopted genetic and pharmacological interventions, in conjunction with immunofluorescent and live cell imaging, to investigate TRPM2-dependent cell death induced by H2O2 and the 42-residue of amyloid β (Aβ42) in cultured hippocampal neurons. H2O2 and Aβ42 induced significant neuronal death, which was reduced or prevented by TRPM2 knock-out (TRPM2-KO), TRPM2 channel inhibitors, or Zn2+ chelator TPEN. H2O2 and Aβ42 induced intracellular Zn2+ increase, lysosomal dysfunction and Zn2+ release, mitochondrial Zn2+ accumulation, dysfunction and ROS generation. Bafilomycin A1-induced lysosomal dysfunction also resulted in mitochondrial Zn2+ accumulation and ROS generation. These events were abolished by TRPM2-KO or suppressed by inhibiting poly(ADP-ribose) polymerase-1 (PARP-1) or TRPM2 channel. Immunofluorescent imaging suggests mitochondrial localization of TRPM2. ADPR enhanced Zn2+ accumulation in isolated mitochondria from wild-type (WT) but not TRPM2-KO neurons. Finally, the inhibition of protein kinase C (PKC) and NADPH oxidases (NOX), particularly NOX1/4, suppressed H2O2/Aβ42-induced neuronal death and Aβ42-induced intracellular Zn2+ increase, lysosomal and mitochondrial dysfunction, and mitochondrial ROS generation. The inhibition of the proline-rich tyrosine kinase 2 (Pyk2) and the downstream MEK/ERK kinases protected against Aβ42-induced neuronal death. Taken together, these results provide evidence to support a vicious positive feedback signalling loop that drives hippocampal neuronal death in response to ROS and Aβ42, in which the TRPM2 channel in mitochondria integrates multiple mechanisms comprising PKC/NOX-mediated ROS generation, lysosomal dysfunction and Zn2+ release, mitochondrial Zn2+ accumulation, mitochondrial dysfunction and ROS generation. In addition, the Pyk2-MEK-ERK signalling pathway is critically involved in Aβ42-induced TRPM2-dependent neuronal death. These findings provide novel insights into the mechanisms underlying neuronal death and cognitive impairment related to ischemic stroke and AD.
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Lange, Ingo. "The TRPM2 ion channel in nucleotide-gated calcium signaling." kostenfrei, 2008. http://d-nb.info/989951200/34.
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Xia, Rong. "TRPM2 Channel : Assembly, Ion permeability, and regulation by interacting proteins." Thesis, University of Leeds, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.511157.
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Syed, Mortadza Sharifah Alawieyah. "Microglial TRPM2 channel activation and its relationship to neurodegenerative diseases." Thesis, University of Leeds, 2017. http://etheses.whiterose.ac.uk/19281/.
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Microglial cell plays a key role in neuroinflammation induced by diverse danger associated molecular patterns (DAMP) molecules, such as Zn2+, Aβ42 and TNF-α, and strongly implicated in neurodegenerative diseases. The molecular mechanisms for neuroinflammation are however not fully defined. Reactive oxygen species (ROS) production is critical in DAMP-induced microglial cell activation and cytokine production. Studies presented in this thesis aimed to investigate, using immunocytochemistry, single cell imaging, cell death and ELISA assays in combination with genetic and pharmacological interventions, the role of ROS-sensitive TRPM2 channel in cell death, cell activation and production of TNF-α in primary microglial cells in response to Zn2+, Aβ42 and TNF-α as well as H2O2. H2O2 (10-300 mM) and Zn2+ (10-300 mM) induced concentration-dependent increases in the intracellular Ca2+ concentration ([Ca2+]i) via Ca2+ influx, which were prevented by TRPM2 knockout (TRPM2-KO) or treatment with TRPM2 inhibitor 2-APB or PARP inhibitor PJ34. Pathological concentrations of H2O2 (100-300 mM) and Zn2+ (100-300 mM) induced substantial cell death that was ablated by TRPM2-KO and treatment with 2-APB or PJ34. Zn2+ also induced ROS production and PARP-1 activation. All these Zn2+-induced effects were suppressed by treatment with PKC inhibitor chelerythrine, NOX inhibitors DPI, GKT137831 or Phox-I2. Zn2+-induced PARP-1 stimulation, increase in the [Ca2+]i and cell death were also inhibited by PYK2 inhibitor PF431396 or MEK/ERK inhibitor U0126. Exposure to Aβ42 (30-300 nM) and TNF-α (10-100 ng/ml) resulted in concentration-dependent TRPM2-mediated Ca2+ influx and increases in the [Ca2+]i, microglial cell activation and TNF-α production. Aβ42 and TNF-α stimulated ROS production and PARP-1 activation. These effects induced by Aβ42 or TNF-α were suppressed by inhibiting PKC and NOX. Moreover, Aβ42/TNF-α induced PARP-1 activation, increase in the [Ca2+]i, microglial cell activation and TNF-α production were attenuated by inhibiting PYK2 and MEK/ERK. In summary, studies provide strong evidence to reveal a critical role for the TRPM2 channel in Ca2+ signalling in microglial cells induced by Zn2+, Aβ42 and TNF-α. TRPM2 channel activation by Zn2+, Aβ42 and TNF-α depends on PKC/NOX-mediated ROS production and PARP-1 activation and is additionally enhanced by the PYK2-MEK-ERK signalling pathway. Such mechanisms are critically involved in cell death in response to Zn2+, or microglial cell activation and TNF-α production in response to Aβ42 and TNF-α. These findings provide novel insights into the role of microglial cells in neuroinflammation and in the pathogenesis of neurodegenerative diseases.
5
Abuarab, Nada Khaled S. "TRPM2 ion channel trafficking and its role in mitochondrial fragmentation and cell death." Thesis, University of Leeds, 2015. http://etheses.whiterose.ac.uk/12490/.
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Mitochondria play a central role in oxidative stress-induced cell death. By increasing the production of reactive oxygen species, such as H2O2, oxidative stress causes mitochondrial fragmentation and apoptosis. It was hypothesised that Transient Receptor Potential Melastatin 2 (TRPM2) channels play a role in mitochondrial fragmentation and cell death. The rationale behind this hypothesis was the published evidence that oxidative stress stimulates TRPM2 channels, resulting in an increase in the cytosolic levels of Ca2+ and Zn2+, and that both these ions are detrimental to mitochondrial health and cell survival. To test the hypothesis, human umbilical vein endothelial cells (HUVECs) and endothelial cells isolated from wild-type and TRPM2 knock-out mice were used. TRPM2 actions were suppressed using pharmacological agents and small interfering RNA (siRNA). Fluorescent reporters were used to examine changes in intracellular ion distribution and organelle morphology. Molecular biology, biochemical and imaging techniques were used to examine the dynamics of ions and organelles. Exposure of HUVECs to H2O2 or high glucose stress led to TRPM2 activation, resulting in extracellular Ca2+ entry, lysosomal membrane permeability (LMP) and the release of lysosomal free Zn2+. Unexpectedly, this was accompanied by the accumulation of Zn2+ in the mitochondria. The rise in mitochondrial Zn2+ led to extensive mitochondrial fragmentation, mitochondrial outer membrane permeabilisation (MMP) and cell death. Silencing of TRPM2 channels with siRNA prevented intracellular Zn2+ redistribution, mitochondrial fragmentation and cell death. Endothelial cells derived from TRPM2 knock-out mice were resistant to oxidative stress-induced mitochondrial fragmentation. Biochemical and immunostaining experiments revealed an unexpected presence of TRPM2 channels in mitochondria, where they mediated mitochondrial Zn2+ uptake. Accumulation of Zn2+ in the mitochondria led to mitochondrial fragmentation by promoting the recruitment of cytoplasmic Drp1, an enzyme responsible for mitochondrial fission. Taken together, the results of this thesis revealed a novel mechanism for how oxidative stress can cause excessive mitochondrial fragmentation and cell death: the mechanism involves activation of TRPM2 channels leading to increased Ca2+ entry, LMP and release of lysosomal Zn2+; Zn2+ thus released is taken up by the mitochondria, leading to Drp1 recruitment, mitochondrial fragmentation and finally cell death. Since mitochondrial fragmentation is associated with several age-related chronic illnesses, including neuronal (Alzheimer’s, Parkinson’s), cardiovascular (atherosclerosis, myocardial infarction) and metabolic/inflammatory (diabetes) disorders, these results suggest that the TRPM2 channel is a novel target that could be explored for therapeutic intervention of age-related illnesses.
6
Kouzai, Daisuke. "Chemical biological studies on oxidation status-sensitive calcium channels." 京都大学 (Kyoto University), 2014. http://hdl.handle.net/2433/188546.
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Ferioli, Silvia [Verfasser], and Barbara [Akademischer Betreuer] Conradt. "Cellular functions of the kinase-coupled TRPM6/TRPM7 channels / Silvia Ferioli ; Betreuer: Barbara Conradt." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1162840501/34.
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8
Massullo, Pam. "Aberrant subcellular targeting of the G185R neutrophil elastase mutant associated with severe congenital neutropenia induces premature apoptosis of differentiating promyelocytes & expression and function of the transient receptor potential 2 (TRPM2) ion channel in dendritic cells." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1172865905.
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Zou, Jie. "Function and modulation of TRPM2 channels." Thesis, University of Leeds, 2013. http://etheses.whiterose.ac.uk/5902/.
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Melastatin-related transient receptor potential 2 (TRPM2) channel is a Ca2+-permeable cation channel that is gated by ADP-ribose (ADPR) and also activated by reactive oxygen species (ROS) such as H2O2. TRPM2 channel are shown to be critically involved in several physiological and pathological cell processes. Previous studies have reported inhibition of the human TRPM2 channel by extracellular acidic pH. However, the underlying mechanism is not fully understood. In the present study, I performed patch-clamp recordings to examine the effect of extracellular acidic pH on ADPR-induced currents in HEK293 cells heterogeneously expressing human TRPM2 (hTRPM2) or mouse TRPM2 (mTRPM2) channels. The results showed that the inhibition was substantially reversible upon brief exposure to acidic pH but became irreversible after prolonged exposure, supporting the mechanism in which protons bind to and inhibit the open TRPM2 channel and the proton-binding induces further conformational changes leading to channel inactivation. Furthermore, the mTRPM2 channel exhibited a lower sensitivity to, and slower kinetics of, inhibition, than the hTRPM2 channel. A residue in the pore region (His-995 in hTRPM2 and Gln-992 in mTRPM2) had a crucial role in determining such species differences. The pharmacology of the TRPM2 channel is poor, with no specific inhibitor. Here, I examined the effects of 48 hit compounds identified from screening chemical libraries on hTRPM2 channels expressed in HEK293 cells. Four compounds inhibited H2O2-induced Ca2+-response with a micromolar to submicromolar potency and abolished ADPR-induced currents at 10 μM, indicating that they act as TRPM2 channel inhibitors. The TRPM2 channel was reported to be functionally expressed in macrophage cells, but its role in mediating ROS-induced Ca2+ signalling and cell death is largely unclear. This study examined the contribution and mechanism of the TRPM2 channel in H2O2-induced Ca2+-responses and cell death in RAW264.7 and differentiated THP-1 macrophage cells and peritoneal macrophage cells isolated from TRPM2+/+ and TRPM2-/- mice. The results showed that TRPM2 channels operated as cell surface Ca2+-permeable channels and constituted the principal Ca2+ signalling mechanism, but played a limited role in cell death. In summary, the results from my study provided useful information to advance the understanding of the pharmacology and functional roles of the TRPM2 channels.
10
Naylor, Jacqueline. "Function and pharmacology of TRPM3 ion channel." Thesis, University of Leeds, 2008. http://etheses.whiterose.ac.uk/330/.
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For many ion channels there are few, if any, pharmacological agents, and even fewer showing specificity. In this study, a set of pharmacological tools were developed to investigate TRPM3, a widely expressed transient receptor potential (TRP) channel for which no functional role has yet been identified. Human TRPM3 was first expressed in HEK 293 cells and shown to be activated by hypo-osmotic challenge or sphingosine, consistent with previous reports. In addition, TRPM3 was activated by pregnenolone sulphate. Hydrophobicity analysis of the TRPM3 amino acid sequence revealed a short and reasonably unique peptide in the 3rd extracellular loop (E3) region, to which polyclonal antiserum (TM3E3) was produced. Extracellular application of TM3E3 inhibited TRPM3 function with a high degree of specificity, having no effect on TRPM2 or example members of other sub-types of mammalian TRP, TRPC5 or TRPV4. The data validate E3-targeting as an approach for production of isoform-specific channel blockers and reveal a specific agent for blocking TRPM3. The cellular and tissue functions of TRPM3 were also investigated. RT-PCR and immunocytochemistry demonstrated TRPM3 expression in human saphenous vein smooth muscle cells, where sphingosine- and pregnenolone sulphate-induced calcium responses were also apparent. These calcium responses could be selectively blocked by TM3E3. Furthermore, TRPM3 activators inhibited matrix metalloproteinase and interleukin-6 secretion, indicating a protective function for TRPM3 in vascular smooth muscle cells. Medium throughput screening systems were employed to screen a library of compounds for further TRPM3 modulators with vascular relevance. Cholesterol, antidepressants, antipsychotics, calmodulin inhibitors, and PIP2 all inhibited TRPM3, whereas nifedipine and elevated temperature activated the channel. TRPM3 appears to be regulated by a large number of different chemicals and mechanisms. In summary, TRPM3 has constitutive, protective, activity which can be suppressed by a multitude of compounds, including known vascular disease factors such as cholesterol.
11
Fernandez, Jose A. "Gating mechanisms of the TRPM* ion channel." Thesis, Queen's University Belfast, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534741.
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Tajino, Koji. "Cutaneous TRPM8 channels are thermostats against cooling." 京都大学 (Kyoto University), 2011. http://hdl.handle.net/2433/142123.
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13
Straub, Isabelle. "Identification and application of novel and selective blockers for the heat-activated cation channel TRPM3." Doctoral thesis, Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-149321.
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TRPM3 (melastatin-related transient receptor potential 3) is a calcium-permeable nonselective cation channel that is expressed in various tissues, including insulin-secreting β-cells and a subset of sensory neurons from trigeminal and dorsal root ganglia (DRG). TRPM3 can be activated by the neurosteroid pregnenolone sulphate (PregS) or heat. TRPM3α2 mice display an impaired sensation of noxious heat and inflammatory thermal hyperalgesia. A calcium-based screening of a compound library identified four natural compounds as TRPM3 blockers. Three of the natural compounds belong to the citrus fruit flavanones (hesperetin, eriodictyol and naringenin), the forth compound is a deoxybenzoin that can be synthesized from an isoflavone of the root of Ononis spinosa (ononetin). The IC50 for the substances ranged from upper nanomolar to lower micromolar concentrations. Electrophysiological whole-cell measurements as well as calcium measurements confirmed the potency of the compounds to block TRPM3 in DRG neurones. To further improve the potency and the selectivity of TRPM3 block and to identify the pharmacophore within the flavanone structure, we conducted a hit optimisation procedure by re-screening a focussed library. The library composed of several flavanones with different substitutions on relevant chemical positions and of representatives from different flavonoid subgroups. Within this secondary screen, we identified isosakuranetin and liquiritigenin as active blockers of PregS-induced Ca2+ entry through TRPM3. Isosakuranetin, a flavanone that can be found in blood oranges and grapefruits, displayed an IC50 of 50 nM, and is the most potent inhibitor of TRPM3 identified so far. The novel compounds exhibited a marked specificity for TRPM3 compared with other thermosensitive TRP channels, and blocked PregS-induced [Ca2+]i signals and ionic currents in freshly isolated DRG neurones. Furthermore, isosakuranetin and hesperetin reduced the sensitivity of mice to noxious heat and PregS-induced chemical pain. Since the physiological functions of TRPM3 channels are still poorly defined, the development and validation of potent and selective blockers is expected to contribute to clarifying the role of TRPM3 in vivo. Considering the involvement of TRPM3 in nociception, TRPM3 blockers may represent a novel concept for analgesic treatment.
14
Georgiev, Plamen. "Functional analysis of Drosophila TRPM." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611931.
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Cao, Tuoxin. "Hydrogen Peroxide and Pharmacological Agent Modulation of TRPV2 Channel Gating." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4848.
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Transient receptor potential vanilloid 2 channel (TRPV2) is a Ca2+-permeable ion channel that is highly expressed in leukocytes but is also present in skeletal and cardiac muscle and endocrine cells. The TRPV2 function is implicated in a number of physiological processes, including bacterial phagocytosis, pro-inflammatory cytokine production, cardiac hypertrophy, and cancer development. TRPV2 knockout mice exhibit a high incidence of perinatal mortality, arguing that the channel plays essential roles in physiology. Despite the importance of TRPV2 for normal homeostasis, the mechanisms that control TRPV2 gating in response to pharmacological agonists, heating, membrane stretch, bioactive lipids and reactive oxygen species (ROS) remain poorly understood. Here we demonstrate that TRPV2 is functionally expressed in microglia (i.e., ‘brain macrophages’) and the microglia-like BV-2 cell line, and demonstrate that the gating of an endogenous TRPV2-like conductance is positively modulated by the bacterial toxin lipopolysaccharide (LPS), which is known to cause pro-inflammatory (M1) activation and increase ROS production by NADPH oxidase. To determine how TRPV2 gating is modulated by ROS, we recorded single channel activity in inside-out patches excised from HEK-293 cells expressing GFP-rTRPV2. Unitary currents elicited by the TRPV2 agonist 2-aminophenyl borinate (2-APB) or cannabidiol (CBD) are linear in monovalent recording solutions and give rise to an estimated unitary conductance of ~100pS, which is similar to TRPV1 but significantly smaller than TRPV3. Intriguingly, we find that although TRPV2 is insensitive to ROS (in the form of exogenously applied H2O2) alone, apparent open probability is synergistically enhanced when H2O2 is applied together with CBD. We identify two intracellular Cys residues that are necessary for TRPV2 responses to H2O2 sensitivity and find that these residues are located close to one another, albeit in different subunits, in the TRPV2 structure, suggesting that ROS promote the formation of an inter-subunit disulfide bond that alters sensitivity to pharmacological agonists. We hypothesize that ROS-dependent modulation of TRPV2 activity may be an important contributor to pro-inflammatory activation of microglia underline central nervous system diseases and that TRPV2 antagonism could be a useful therapeutic strategy in the treatment of neuroinflammation.
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Kaiser, Simone. "Identification and characterization of the ion channel TRPM8 in prostate cancer." Doctoral thesis, [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972610359.
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Melanaphy, D. "Expression and function of the TRPMB ion channel in the vasculature." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558085.
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Luu, Charles T. "TRPM7 channels as a bioassay of internal and external Mg2+." Wright State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=wright1572015043215704.
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Majeed, Yasser. "Chemical modulation of human TRPC and TRPM ion channels." Thesis, University of Leeds, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.515551.
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Viñuela-Fernández, Ignacio. "Equine laminitis pain and modulatory mechanisms at a potential analgesic target, the TRPM8 ion channel." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/8728.
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Chronic neuropathic pain, resulting from dysfunction of the nervous system, is a clinical concern in both humans and animal patients. Neuropathic pain is characterised by spontaneous pain, hypersensitivity, manifested as hyperalgesia and allodynia, and refractoriness to conventional analgesics such as non-steroidal anti-inflammatory drugs, thus representing an unmet therapeutic need. Equine laminitis is a disease that involves the disruption of the dermoepidermal junction within the hoof, leading to severe pain and lameness, with poor responsiveness to anti-inflammatory therapy. We developed a Quantitative Sensory Testing method, using a novel hydraulically-powered feedbackcontrolled hoof tester, in order to provide an objective tool for the assessment of mechanical hyperalgesia in laminitic horses. Hoof Compression Thresholds of laminitic horses were significantly lower than those of normal horses and variance component analysis of the data confirmed the reliability of the method. In order to investigate mechanisms underlying laminitis pain, we performed histological studies of peripheral nerves innervating the hoof. Electron micrographic analysis of the digital nerve of laminitic horses revealed a significant reduction in the number of unmyelinated and myelinated fibres together with abnormal morphology. Additionally, cell bodies of sensory neurons innervating the hoof in cervical C8 dorsal root ganglia showed an upregulated expression of the nerve injury marker activating transcription factor-3 (ATF3), neuropeptide Y (NPY), and the TRPM8 channel; each of which has been associated with laboratory models of neuropathic pain. Previous work has shown that, in a rodent model of neuropathic pain, the TRPM8 channel is upregulated in sensory neurons and its activation by cool temperature, menthol or icilin leads to reversal of the hypersensitive pain state. Further investigation of TRPM8-channel mediated analgesia was aimed at uncovering the molecular mechanisms involved in the activation of this system in sensitised states. It was hypothesised that serotonin, released following inflammation and nerve damage, can enhance TRPM8 channel activity through peripheral 5-HT1B receptors. Calcium fluorometry carried out in HEK293 cells transfected with the TRPM8 channel and the 5-HT1B receptor revealed that coadministration of a 5-HT1B receptor agonist facilitated the activation of the TRPM8 channel by icilin. Moreover, it appears that this effect is mediated through phospholipase D1 (PLD1), possibly leading to increased production of phosphatidylinositol (4,5-) bisphosphate (PIP2), a known positive modulator of TRPM8 channel activity. In vitro co-immunoprecipitation studies suggested that the TRPM8 channel, the 5-HT1B receptor and PLD1 physically interact with each other, further providing a molecular basis for their functional co-operation. Calcium imaging carried out in cultured rat DRG cells showed that the 5-HT1B receptor-mediated enhancement of icilin responses at the TRPM8 channel also occurs in sensory cells and is reversed by inhibition of PLD1. Moreover, TRPM8 and the 5-HT1B receptor appear to be physically associated in vivo as shown by their co-immunoprecipitation from spinal cord homogenates. Assessment of nociceptive behavioural reflexes following intrathecal injection of selective pharmacological agents provided further support for the idea of 5-HT1B receptor facilitation of TRPM8 channel responses in vivo. In addition to providing novel evidence of a neuropathic component to equine laminitis and validation of a novel QST method for pain assessment in horses, this study reveals for the first time a physical and functional interaction between the 5-HT1B receptor and the TRPM8 channel.
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Mak, Stephanie Wai Yin. "Modulation of temperature sensitive ion channels TRPV1 and TRPM8 by Bradykinin." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611520.
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Wu, Yu [Verfasser], and Peter [Akademischer Betreuer] Heisig. "Ion channel TRPM4 activity and cardiac conduction disease / Yu Wu. Betreuer: Peter Heisig." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2012. http://d-nb.info/1030365644/34.
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Liu, Pin. "Fat Taste Transduction in Mouse Taste Cells: The Role of Transient Receptor Potential Channel Type M5." DigitalCommons@USU, 2010. https://digitalcommons.usu.edu/etd/824.
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A number of studies have demonstrated the ability of free fatty acids to activate taste cells and elicit behavioral responses consistent with there being a taste of fat. Here I show for the first time that long chain unsaturated free fatty acid, linoleic acid, depolarizes taste cells and elicits a robust intracellular calcium rise via the activation of transient receptor potential channel type M5. The linoleic acid-induced responses depend on G protein-phospholipase C pathway indicative of the involvement of G protein-coupled receptors in the transduction of fatty acids. Mice lacking transient receptor potential channel type M5 exhibit no preference for and show reduced sensitivity to linoleic acid. Together, these studies show that transient receptor potential channel type M5 plays an essential role in fatty acid transduction and suggest that fat may reflect a bona fide sixth primary taste. Studies to identify the types of taste cells that respond to fatty acids show that both type II and type III taste cells express fatty acid-activated receptors. Fatty acids elicit robust intracellular calcium rise primarily in type II taste cells and a subset of type III taste cells. However, a significant subset of type II taste cells respond to high potassium chloride, which has been broadly used as the indicator for type III taste cells as well, suggesting the expression of voltage-gated calcium channels in these cells. This finding conflicts with previous studies that type II taste cells lack voltage-gated calcium channels. To explore if voltage-gated calcium channels are expressed in subsets of type II taste cells, transgenic mice with type II or III taste cells marked by green fluorescent proteins are used. Results show that a subset of type II taste cells exhibit voltage-gated calcium currents, verifying the expression of voltage-gated calcium channels in these cells. These results question the utility of being able to use high potassium chloride solution to identify unequivocally type III taste cells within the taste buds. A model for the transduction of fatty acids in taste cells consistent with these findings and our previous data is presented.
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Wang, Qian, and 王倩. "Mechanistic study of the transient receptor potential melastain 2 (TRPM2)-Ca²⁺ signaling in ROS induced switch between apoptosis and autophagy." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/206750.
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Autophagy is a major catabolic pathway for maintaining cell homeostasis through degradation and recycle of macromolecules and organelles. Autophagy can be activated under environmental stress conditions, including reactive oxygen species (ROS). TRPM2, a non-selective trans-membrane calcium channel, can be activated by ROS that, in turn, leads to intracellular 〖Ca〗^(2+) increase through 〖Ca〗^(2+) influx. It is well known that ROS regulates autophagy, and vice versa. Yet, the molecular mechanisms underlying the interplay between ROS and autophagy remain elusive. Here we studied the role of TRPM2-mediated 〖Ca〗^(2+) influx in interplay between ROS and autophagy.
From our study, we found that ROS activated TRPM2 for 〖Ca〗^(2+) influx via ADPR to inhibit early autophagy induction, which ultimately led to apoptosis in TRPM2 expressing cancer cell lines. On the other hand, ROS induced autophagy, not apoptosis, for cell survival in cancer cell lines which do not express TRPM2, and autophagy inhibition, either by ATG5 knockdown or by treating cells with bafilomycin A1 (an autophagy inhibitor), converted cells to apoptosis upon ROS treatment. In addition, ROS dramatically changed mitochondrial morphology, increased mitochondrial 〖Ca〗^(2+) content, and abolished mitochondrial membrane potential in TRPM2 expressing cells. Moreover, we found that ROS-induced Ca2+ influx via TRPM2 actually activated calmodulin-dependent protein kinase II (CaMKII) to phosphorylate Ser295 on Beclin1. Phosphorylated Beclin1, in turn, decreased the association between Beclin1 and VPS34, but induced the binding between Beclin1 and BCL-2. In summary, our data demonstrated that the TRPM2/〖Ca〗^(2+)/CaMKII/ Beclin1 cascade is the molecular switch between autophagy and apoptosis in response to ROS. Since dysregulation of ROS and autophagy has been associated with a variety of human diseases, e.g. cancer, neurological disorders, heart diseases, and liver diseases, manipulating the TRPM2/〖Ca〗^(2+)/CaMKII/ Beclin1 cascade should provide novel treatment option for these diseases.published_or_final_version
Physiology
Doctoral
Doctor of Philosophy
25
Gueffier, Mélanie. "Rôle du canal TRPM4 dans l'hypertrophie cardiaque : utilisation d'un modèle d'entraînement." Thesis, Montpellier, 2015. http://www.theses.fr/2015MONTT035.
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Le muscle cardiaque est un organe qui s'adapte à différents stress hémodynamiques en activant la synthèse protéique et en augmentant la taille des cardiomyocytes, résultant sur le développement d'une hypertrophie cardiaque. L'objectif de cette thèse est d'étudier le rôle potentiel du canal TRPM4 dans différents types d'hypertrophie cardiaque. Une altération du Ca2+ diastolique est à l'origine du signal initial activant les voies de signalisation d'une hypertrophie cardiaque délétère de type pathologique telle que la voie de la calcineurine-NFAT et la ré-expression de gènes fœtaux. Cette hypertrophie est alors compensatrice et vise à préserver la fonction de pompe du myocarde. Cette altération peut être conduite par divers stimulis tels qu'une augmentation de l'angiotensine II ou par des pathologies cardiovasculaires telles que l'infarctus du myocarde et l'hypertension. Cependant, une hypertrophie cardiaque bénéfique est également décrite dans la littérature, notamment lors des stades de développement du myocarde lors de l'embryogénèse ou en encore en réponse à une activité physique modérée régulière. Elle se caractérise par l'activation d'une toute autre voie de signalisation qu'est la voie de l'IGF-1-PI3K-Akt engendrée par une augmentation du taux de facteur de croissance qu'est l'insulin growth factor-1. Ces voies de signalisation ont été largement décrites dans la littérature et s'entrecroisent. Le canal TRPM4 est un canal cationique non sélectif perméable de manière égale aux ions Na+ et au K+, imperméables au Ca2+, mais activé par le Ca2+ intracellulaire. Dans le système immunitaire, il régule négativement l'entrée de Ca2+ et ce canal apparaît donc impliqué dans de nombreuses fonctions cellulaires dépendantes du Ca2+ dans différents types cellulaires. Par l'utilisation de deux modèles d'hypertrophie cardiaque, un physiologique généré par quatre semaines d'entraînement en endurance et un pathologique suite à un infarctus du myocarde induit par la ligature de l'artère coronaire gauche sur des souris wild-type et knock-out (KO) pour le canal TRPM4, nous avons mis en évidence une augmentation d'expression fonctionnelle du canal TRPM4 au sein du ventricule gauche associée à une régulation négative d'entrée de Ca2+. Le canal TRPM4 étant un régulateur de l'homéostasie calcique des cardiomyocytes, son expression fonctionelle après l'infarctus du myocarde ainsi que l'entraînement favorise l'activation de la voie de l'IGF-1-PI3K-Akt et prévient partiellement l'activation de la voie de la Calcineurine-NFAT et le développement d'une hypertrophie cardiaque pathologique, notamment dans le modèle d'infarctus du myocarde. En effet, en absence d'expression du canal, l'entrée de Ca2+ n'étant plus régulée, la voie de la Calcineurin-NFAT est favorisée. Mots clés : TRPM4, hypertrophie cardiaque, entraînement, IGF-1-PI3K-Akt, CalcineurineAbstract: Cardiac muscle is an organ that adapts to different hemodynamic stress by activating protein synthesis and increasing cardiomyocytes size, resulting in cardiac hypertrophy. The objective of this PhD is to study the potential role of TRPM4 channel in different types of cardiac hypertrophy. Impaired diastolic Ca2+ is responsible for the initial signal activating signaling pathways in a deleterious cardiac hypertrophy pathological type such as Calcineurin-NFAT pathway and the re-expression of fetal genes. This hypertrophy is first compensatory and preserves the myocardial pump function. This alteration can be carried out by various stimuli such as increased angiotensin II or by cardiovascular diseases such as myocardial infarction and hypertension.However, a beneficial cardiac hypertrophy is also described in the literature, especially during development stages during embryogenesis or even in response to regular moderate physical activity. It is characterized by the activation one different signaling pathway, the IGF-1 - PI3K –Akt, generated by an increase in growth factor levels that is the insulin growth factor -1. These signaling pathways have been widely described in the literature and cross-talking. TRPM4 channel is a nonselective cation channel permeable equally to Na+ and K+, impermeable to Ca2+ but activated by the intracellular Ca2+. In the immune system, it downregulates Ca2+ entry and therefore appears to be involve in many Ca2+-dependent cellular functions in different cell types. By the use of two models of cardiac hypertrophy, a physiological generated by four weeks of training in endurance and pathological after myocardial infarction induced by ligation of the left coronary artery on wild-type and knockout mice -out (KO) for TRPM4 channel, we have demonstrated a functional expression increased TRPM4 channel within the left ventricle associated with down-regulation of Ca2 + entry. TRPM4 the channel being a regulator of calcium homeostasis in cardiomyocytes functional expression after myocardial infarction as well as the drive promotes the activation of the pathway of IGF-1-PI3K-Akt and partially prevents the pathway activation of the NFAT-calcineurin and the development of pathological cardiac hypertrophy, in particular myocardial infarction model. Indeed, in the absence of expression of the channel, the Ca2 + is not regulated, the path of Calcineurin-NFAT is favored. Keywords: TRPM4, cardiac hypertrophy, training, IGF-1-PI3K-Akt, calcineurin
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Mellott, Alayna N. "Divalent Metal Cation Entry and Cytotoxicity in Jurkat T Cells: Role of TRPM7 Channels." Wright State University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=wright1597319673881729.
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Hampe, Sarah [Verfasser], and Ingrid [Akademischer Betreuer] Boekhoff. "Domain-specific role of the channel-kinase TRPM7 in cell signaling / Sarah Hampe ; Betreuer: Ingrid Boekhoff." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1225682487/34.
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Huynh, Kevin Weijian. "Structural Analysis of TRPV2 by Cryo-Electron Microscopy Reveals Regulatory Diversity Among the ThermoTRPV Channels." Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1467996438.
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Abdulkareem, Zana Azeez. "SK potassium and TRPM7 ion channel role in CNS cell survival and breast cancer cell death decisions." Thesis, Cardiff University, 2015. http://orca.cf.ac.uk/80343/.
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Cell survival is modulated by a cocktail of ion channels engaging cell life and death decisions through controlling key cellular messages such as apoptosis and proliferation. Unnatural regulation of these processes results in various disorders, for example neurodegenerative diseases, as well as the cancers. Nowadays, these pathologies are affecting millions of people per year in the world. Potassium (K+) ion channels appear to play a potent role in such illnesses since they can control many cellular gates in cell physiology such as ionic homeostasis and signalling cascades. Amongst the K+ channels, small (SK1-3) and intermediate (SK4) conductance Ca2+-activated potassium ion channels have recently been shown to save cells, thereby protecting mitochondrial function which serves as a cell survival platform. In the case of other ion channels, for instance transient receptor potential melastatin 7 (TRPM7), it is also repeatedly stated that such membrane channels shows an impressive and differential role in excitable and non-excitable cell survival. This channel also modulates ionic homeostasis of crucial ions in cellular physiology such as Ca2+. This study reveals that central nervous system (CNS) and breast cancer cells differentially express SK1-4 ion channel subtypes, and their functional presence is pharmacologically confirmed, however, in most cases these results were further clarified through small interference RNA (siRNA) method. Similarly, functional TRPM7 channel expression in CNS cells is also confirmed. In the CNS, SK1-4 channel activation rescues neurons from oxidative stress, whereas, TRPM7 channel inhibition protects CNS cells from this hydrogen peroxide (H2O2) harmful effect, as well as hypoxia and apoptosis, so improving cell survival. Excitingly, SK1-4 channels differentially exist between wild-type and Huntington’s affected mouse striatal cells, where diseased cells lack SK1-3 channels, key players in action potential activity. Interestingly, SK2 or SK3 channel subtypes are also functionally expressed in breast cancer cells with various phenotypes. This study established that these ion channels are powerful agents in a survival role, in fact controlling growth through cross-talk with an apoptotic avenue “intrinsic pathway”. SK2 or SK3 channel activation enhances cell viability, while its inhibition dampens cell growth. It is very noteworthy that SK2 and SK3 channels are not expressed in non-tumorigenic breast cells. In brief, SK1-4 and TRPM7 molecules are clearly implicated in the survival of diverse cell types through an apoptotic route, indicating that these ionic regulators are promising targets in channelopathies related to cellular degeneration and growth.
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Curry, Haley Nicole. "Characterization of a Conserved Transient Receptor Potential Channel Supporting Spermatogenesis in Planarian Flatworms." Wright State University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=wright1589976835122505.
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Zhang, Yanhui, and 张雁惠. "Modulation of transient outward potassium channels by protein tyrosinekinases and demonstration of TRPC and TRPM channels in human atrialmyocytes." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47161644.
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My PhD project investigated the regulation of human cardiac transient outward potassium current (Ito) by protein tyrosine kinases (PTKs) and the functional expression of transient receptor potential (TRP) channels in human atrial myocytes to make an advanced understanding of human cardiac electrophysiology and pathophysiology.
The modulation of human cardiac Itoby PTKs was studied in human atrial myocytes and HEK 293 cells expressing hKv4.3 (coding human cardiac Ito). We found that the broad-spectrum PTK inhibitor genistein, the selective EGFR kinase inhibitor AG556, and the Src-family kinases inhibitor PP2 inhibited human atrial Itoand the inhibitory effect was countered by the protein tyrosine phosphatase (PTP) inhibitor orthovanadate. Similar results were observed in hKv4.3-HEK cells. Interestingly, tyrosine phosphorylation of hKv4.3channels was reduced by genistein, AG556, and PP2,and the reduction was antagonized by orthovanadate. The mutant Y136F of hKv4.3 lost the inhibitory response to AG556, whileY108F lost the response to PP2.The double mutant Y108F-Y136F hKv4.3 failed to respond to both AG556 and PP2, and exhibited a dramatic reduction of tyrosine phosphorylation. These results indicate that native cardiac Itois regulated by both EGFR and Src family kinases.
In the second part, we studied whether TRPC channels would mediate the nonselective cation current described previously in human atrial myocytes. It was found that TRPC1 channel activator thapsigargin activated the current, and the effect was suppressed by La3+or prevented by intracellular anti-TRPC1 antibody. Endothelin-1 and angiotensin II stimulated the current, andthe effect was inhibited by La3+and/or 2-APB. RT-PCR and Western blot analysis revealed that in addition to the TRPC1 channels mediating the nonselective cation current, the components of store-operated Ca2+channels (SOCs), STIM1 and Orai1 were abundantly expressed in human atria. The interaction of TRPC1, STIM1, and Orai1 was confirmed by co-immunoprecipitation. Interestingly, we found that protein expression of TRPC1 and STIM1, but not Orai1, was up-regulated in human atria with atrial fibrillation.
The third part of the project determined whether TRPM7 channels were expressed in human atrial myocytes, since this channel was reported in human atrial fibroblasts, conferring atrial fibrosis in human atria with atrial fibrillation. We found a TRPM7 -like current which was potentiated by acidic pH, and inhibited by La3+and 2-APB, and a Ca2+-activated TRPM4 current. RT-PCR and Western blot analysis confirmed the expression of TRPM7 and TRPM4 channels in human atria. Moreover, we found TRPM7 protein, but not TRPM4 protein was significantly up-regulated in human atria with atrial fibrillation, suggesting the potential participation of TRPM7 channels in atrial remodeling of human atria with atrial fibrillation.
Collectively, this PhD thesis project has demonstrated for the first time that human cardiac Itois modulated by EGFR kinase and Src kinases via phosphorylating Y136and Y108, respectively. TRPC1 channels mediate the nonselective cation current and SOCs.TRPM7 channels are expressed in human atrial myocytes. The up-regulation of TRPC1, STIM1, and TRPM7 channels in human atria with atrial fibrillation suggest that they are likely involved in atrial electrical and/or structure remodeling in patients with atrial fibrillation.published_or_final_version
Medicine
Doctoral
Doctor of Philosophy
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Uriu, Yoshitsugu. "Biochemical and biophysical characterization of Ca2+ channel complexes in neurotransmission." 京都大学 (Kyoto University), 2010. http://hdl.handle.net/2433/126814.
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Mittermeier, Lorenz [Verfasser], and Dietmar [Akademischer Betreuer] Martin. "The kinase-coupled TRPM7 channel is the central gatekeeper of intestinal mineral absorption / Lorenz Mittermeier ; Betreuer: Dietmar Martin." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1185979298/34.
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Vettore, Valentina [Verfasser], and Alexander [Akademischer Betreuer] Dietrich. "TRPM7 in T-cell signaling : kinase-coupled ion channel in immune system homeostasis / Valentina Vettore ; Betreuer: Alexander Dietrich." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1196009090/34.
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Lucius, Alexander [Verfasser]. "Characterization of temperature-sensitive transient receptor potential channel melastatin 8 (TRPM8) in cultivated human ocular surface cells / Alexander Lucius." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2017. http://d-nb.info/1126503886/34.
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Yang, Heng. "TRPM4, a non selective cation-permeable channel regulates Foxp3+ regulatory T cells suppressive function and survival trough modulating calcium influx." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA114840.
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TRPM4, un canal cationique non-sélective activé par le Ca2+ intracellulaire, est un acteur moléculaire important impliqué de la régulation du signal calcique et l’activation des lymphocytes T conventionnels mais son rôle dans la fonction des lymphocytes T régulateurs (Tregs Foxp3+) reste inconnu. Dans un modèle de souris transgéniques dans lequel le gène Trpm4 a été sélectivement invalidé dans la population des Tregs Foxp3+ (souris Foxp3(YFP)Cre+Trpm4flox/flox), nous avons démontré dans différents modèles in vivo d’inflammation aiguë et chronique que TRPM4 contrôle la fonction suppressive et la mort de ces cellules. Dans le modèle de fibrosarcome induit par le méthylcholanthrène (3-MCA) ou implanté (modèle MCA205), dans lequel le rôle des Tregs est documenté, l’absence de fonction de TRPM4 induit une diminution significative de l’incidence et de la croissance tumorale. Dans l’environnent inflammatoire chronique et hypoxique de ces tumeurs, l’expression de TRPM4 protège les Tregs infiltrant la tumeur de la mort cellulaire induit par l’ATP extracellulaire et stimule ainsi le développent et la progression tumorale. L’absence d’expression de TRPM4 dans les Tregs stimule la réponse anti-tumorale médiée par l’IFNg et induit la régression des tumeurs. En conclusion, en inhibant l’entrée de Ca2+ extracellulaire, TRPM4 régule négativement les fonctions suppressives des Tregs et protège ces cellules de la mort cellulaire induite par l’activationTRPM4, a Ca2+-activated non-selective cation ion channel is an important regulator of Ca2+ signaling and cell activation in conventional T cells, but its role in Foxp3+ Tregs function remains unknown. Using a model in which Trpm4 gene was selectively invalidated in Foxp3+ Tregs population (Foxp3(YFP)Cre+Trpm4flox/flox mice) we have shown in different in vivo models of acute and chronic inflammation that TRPM4 is an important regulator of Tregs functions and survival. In a model of primary carcinogenesis induced by methylcholantrene (3-MCA) or implanted fibrosarcoma (MCA205 model), in which Tregs role has been documented, lack of TRPM4 expression and function induced significantly decreased incidence and tumor growth. We found that within chronic inflammatory and hypoxic tumor microenvironment, TRPM4 protected Tregs from ATP-induced cell death and therefore promoted tumor initiation and progression. In contrast, TRPM4 deficiency in Tregs favored IFN-g-mediated spontaneous anti-tumor immune response. Thus, through inhibiting Ca2+ influx, TRPM4 acts as a negative modulator of Tregs suppressive functions and protects Tregs from activation-induced cell death
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Kaiser, Simone [Verfasser], Matthias [Gutachter] Dürst, Thomas [Gutachter] Börner, and Wolfgang [Gutachter] Kemmner. "Identification and characterization of the ion channel TRPM8 in prostate cancer / Simone Kaiser ; Gutachter: Matthias Dürst, Thomas Börner, Wolfgang Kemmner." Berlin : Humboldt-Universität zu Berlin, 2004. http://d-nb.info/1206182024/34.
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Bauerle, Erin Ruane. "ASSOCIATION OF MASSETER MUSCLE CACNA2D1, CACNA1S, GABARAP, AND TRPM7 GENE EXPRESSION IN TEMPOROMANDIBULAR JOINT DISORDERS." Master's thesis, Temple University Libraries, 2016. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/392863.
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Oral BiologyM.S.
A major physiological risk factor of temporomandibular disorders (TMD) is sensitization of peripheral and central nervous system pain processing pathways. Calcium channel, voltage-dependent, alpha-2/delta subunit-1 (CACNA2D1) has a crucial role in relaying nociceptive information in the spinal dorsal horn. Up-regulation of CACNA2D1 results in abnormal excitatory synapse formation and enhanced presynaptic excitatory neurotransmitter release. Blocking CACNA2D1 with gabapentinoid-class drugs relieves orofacial hypersensitivity. Drs. Foley, Horton, and Sciote previously reported that in a small sample group (n=12), CACNA2D1 expression was greater in males than females, but increased in women with TMD. The objectives of this study are to corroborate these data and investigate expression patterns of other ion channel and conducting system genes. Additionally, since the null polymorphism ACTN3-577XX associates with muscle fiber microdamage during eccentric contraction, we tested for possible gene associations with ACTN3-R577XX genotypes. Masseter muscle samples came from human subjects (n=23 male; 48 female) with malocclusions undergoing orthognathic surgery. This population had skeletal disharmony of the jaws and thus was prone to eccentric contraction. Three males and eighteen females were diagnosed with localized masticatory myalgia. Muscle total RNA was isolated and CACNA2D1, CACNA1S, GABARAP, and TRPM7 expression was quantified using RT-PCR. Expression of these genes were compared based on TMD status and various characteristics that may influence TMD including: sex, age, facial symmetry, sagittal dimension, vertical dimension, ACTN3-577 genotype and fiber type. CACNA2D1 expression differed significantly between sexes, overall (p<0.02), and without TMD (p=0.001). Women with (n=13) and without (n=23) TMD differed significantly (p<0.03). CACNA2D1 expression was also significantly higher (p=0.031) in subjects below age 25. Similarly, GABARAP expression was significantly higher (p=0.001) for patients younger than 25 and for patients less than or equal to age 18 (p=0.013). Otherwise, CACNA1S, TRPM7 and GABARAP differences were not significant. GABARAP expression differed, but not significantly by sex and for the ACTN3-577XX-null genotype. In a population of malocclusion patients, masseter muscle CACNA2D1 expression is significantly higher than CACNA1S, TRPM7, and GABARAP. CACNA2D1 expression is greater in males than females without TMD. However, CACNA2D1 expression increases significantly in females with TMD-associated myalgia. This may support evidence for calcium channel regulation of nociception differences seen between sexes in TMD. It was also found that expression of CACNA2D1 and GABARAP is significantly higher in younger subjects. Additionally, observations presented here suggest potential influence of ACTN3-null condition on function of GABARAP.
Temple University--Theses
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Lefebvre, Thibaut. "Rôle du canal TRPM7 dans la prolifération des cellules stellaires pancréatiques humaines activées." Electronic Thesis or Diss., Amiens, 2019. http://www.theses.fr/2019AMIE0057.
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L'expression et/ou l'activation des canaux ioniques, protéines transmembranaires qui contrôlent de nombreuses fonctions cellulaires, sont altérées dans le cancer. Nous avons déjà montré l'implication des canaux TRPM7 (Transient Receptor Potential Melastatin-related 7) dans la migration et l'invasion des cellules d’ACP (Rybarczyk et al. 2012 et 2017). Par contre, son expression et son rôle dans les cellules stellaires pancréatiques sont inconnus. Au cours de ce travail nous avons démontré que le canal TRPM7 est impliqué dans la prolifération et le maintien de l'homéostasie magnésique dans les CSP. Le canal régule la prolifération cellulaire par l'activation magnésium dépendante de la voie PI3K/AKT permettant la répression de P53 et GSK3, la synthèse de CDK2 et PCNA, et la transition G1-S du cycle cellulaire. Nous avons également démontré que le canal TRPM7 régule l'expression de l'α-SMA, principal marqueur d'activation des CSP, en modulant l'activation de la voie ERK de façon dépendante du magnésium. Enfin nos résultats indiquent que l'expression du canal TRPM7 varie en fonction du niveau d'activation des CSP. L'ensemble de nos résultats suggèrent que le canal TRPM7 pourrait constituer un biomarqueur important concernant l'activation et la prolifération des CSPPancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest cancers with a 5 years survival rate under 5%. PDAC development and aggressivness involve pancreatic stellate cells (PSC) activation occurring during desmoplasia. PSC activation induces α-SMA expression, increases proliferative capacities of the CSP, and leads to cancer growth and metastasis. Ion channels are involved in many cellular mechanisms including cell migration, invasion and proliferation. We previously described the role of TRPM7 in PDAC cell invasion and migration (Rybarczyk et al. 2012 and 2017) but its role in PSC remains unknown. Here we show that TRPM7 is involved in magnesium homeostasis and PSC cell proliferation throughPI3K/AKT pathway activation by magnesium. TRPM7 mediated magnesium entry inducing PI3K/AKT pathway activation and leading to P53 and GSK3 inhibition, and CDK2 and PCNA upregulation inducing G1 to S transition. Our results show that TRPM7 is also involved in α-SMA expression by regulating ERK activation in a magnesium dependent manner. PSC activation also regulates TRPM7 expression. Taking together our results show TRPM7 as a potential biomarker for CSP activation and proliferation in PDAC
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Straub, Isabelle [Verfasser], Rudolf [Gutachter] Rübsamen, and Michael [Gutachter] Schaefer. "Identification and application of novel and selective blockers for the heat-activated cation channel TRPM3 / Isabelle Straub ; Gutachter: Rudolf Rübsamen, Michael Schaefer." Leipzig : Universitätsbibliothek Leipzig, 2014. http://d-nb.info/123878819X/34.
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銭, 年超. "成長板軟骨細胞におけるTRPM7チャネルを介する自発的Ca2+変動." Kyoto University, 2018. http://hdl.handle.net/2433/232324.
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Skandarani, Nadia. "Développement de nanocapsules lipidiques pour la délivrance de principes actifs." Thesis, Besançon, 2014. http://www.theses.fr/2014BESA2071/document.
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Le développement des nanotechnologies dans le domaine médical a suscité un engouement considérable ces dernières années, notamment l’utilisation de nanoparticules pour la vectorisation de principes actifs. Les nanoparticules offrent des perspectives uniques pour la vectorisation et la délivrance de principes actifs qu’ils soient des gènes (thérapie génique),des anti-cancéreux (chimiothérapie) ou encore des agents photosensibilisateurs (photothérapie dynamique, TPD). Le défi majeur reste cependant l’acheminement des molécules thérapeutiques jusqu’à leur site d’action, tout en gardant leur intégrité ainsi que leur effet thérapeutique.L’axe de recherche de cette thèse est l’utilisation des nanocapsules lipidiques comme plateforme multifonctionnelle pour la délivrance de principes actifs. Un des objectifs étant le développement de nanocapsules lipidiques, stables de point de vue physico-chimique, et fonctionnalisées avec du polyéthylèneimine capables de délivrer efficacement un plasmide ADN et un anti-cancéreux (paclitaxel) dans le cadre d’une thérapie combinée. Les applications de ces nanovecteurs pour la transfectionde gènes et la vectorisation de chimiothérapeutique in vitro ont été réalisées.Par ailleurs, l’aptitude de nanocapsules lipidiques à vectoriser des agents photosensibilisants pour la thérapie photodynamique a été aussi étudiée in vitro, et les résultats ont montré que l’encapsulation de deux molécules de PS dans les nanocapsules permet une synergie de l’effet photodynamique tout en gardant les propriétés physico-chimiques de chaque PS. Enfin, l’encapsulation d’un agoniste au canal ionique TRPM8, le menthol, fait l’objet du dernier chapitre. L’étude par imagerie calcique du relargage de cette molécule lipophile in vitro a permis de confirmer le potentiel des NCL comme nanovecteurs de principes actifsThe development of nanotechnology in the medical field has attracted considerable interest in recent years, including the use of nanoparticles for drug delivery. Nanoparticles offer unique opportunities for delivery of active drugs such as genes (gene therapy), anti-cancer (chemotherapy) or photosensitizers (photodynamic therapy, PDT). The major challenge, however, remains the delivery of therapeutic molecules to their site of action while keeping their integrity and their therapeutic effect.The research focus of this thesis is the use of lipid nanocapsules as a multifunctional platform for the delivery of drugs. One goal is the development of stable lipid nanocapsules, functionalized with polyethyleneimine and capable of effectively delivering a plasmid DNA and an anti-cancer (paclitaxel) as part of a combination therapy. The applications of these nanocarriers for transfection and delivery of chemotherapeutic were performed in vitro.Moreover, the ability of lipid nanocapsules to encapsulate photosensitizers for photodynamic therapy has been studied in vitro, and the results showed that the encapsulation of two molecules of PS in the nanocapsules allows a synergy photodynamic effect while protecting the PS from photo degradation.Finally, encapsulating an ion channel TRPM8 agonist (menthol) is the subject of the last chapter. The study by calcium imaging of the release of this lipophilic molecule in vitro confirmed the potential of lipid nanocapsules as nanocarriers of drugs
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Fearey, Brenna C. [Verfasser]. "The role of the TRPM4 channel in hippocampal synaptic transmission and the development of genetically-encoded tools for mapping neuronal and synaptic activity : Die Rolle des TRPM4-Kanals bei der synaptischen Übertragung im Hippocampus und die Entwicklung genetisch kodierter Werkzeuge zur Kartierung neuronaler und synaptischer Aktivität / Brenna C. Fearey." Hamburg : Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky, 2020. http://d-nb.info/1221276395/34.
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Ramos-Filho, Antonio Celso Saragossa 1985. "Participação do receptor de potencial transiente vanilóide do tipo 4 (TRPV4) e do melastatina do tipo 8 (TRPM8) nas disfunções miccionais do diabetes em camundongos." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/312586.
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Orientador: Edson AntunesTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Os receptores TRPV4 e TRPM8 são expressos no urotélio e em fibras aferentes sensitivas da bexiga. Fisiologicamente, a ativação mecânica do receptor TRPV4 na parede da bexiga participa do controle miccional. Em doenças de origem inflamatória, esses receptores adquirem funcionalidade importante. As disfunções da bexiga no diabetes podem estar associadas a alterações ao nível de detrusor, inervação e urotélio. A disfunção urotelial parece ser a responsável por desencadear as alterações neurais e musculares da bexiga. Assim, o objetivo do presente estudo foi investigar os mecanismos fisiopatológicos da ativação dos receptores TRPV4 e TRPM8 no estado diabético em camundongos. Para tanto, dividimos o estudo em duas etapas, sendo que na primeira avaliamos a participação dos receptores TRPV4 e TRPM8 nos mecanismos contráteis e relaxantes do detrusor isolado de animais controles e knockout para esses canais. Em uma segunda etapa estudamos a ativação desses canais em camundongos diabéticos pela injeção intraperitoneal de estreptozotocina (180 mg/Kg) por 4 semanas. Em fragmentos do detrusor isolados de camundongos mostramos que o agonista do receptor TRPV4, GSK1016790A, causou resposta contrátil dependente da concentração. Por outro lado, quando os tecidos foram contraídos com solução despolarizante de KCl, o GSK1016790A causou relaxamento da preparação. No detrusor isolado de animais TRPV4-/- verificamos hipercontratilidade ao carbacol (agonista muscarínico) e à estimulação elétrica, assim como redução no relaxamento ao agonista ?-adrenérgico não-seletivo, isoprenalina. Estes efeitos não foram obtidos com os antagonistas dos receptores TRPV4, RN1734 e HC067047. A indução do diabetes causou nocicepção mecânica e aumento da proporção entre bexiga e peso corpóreo após 4 semanas da injeção. A avaliação miccional dos animais diabéticos mostrou aumento da capacidade, frequência urinária e das contrações involuntárias da bexiga. Observamos ainda hipercontratilidade do detrusor ao carbacol, à estimulação elétrica e ao KCl. A indução do diabetes em animais TRPV4-/- não modificou as disfunções "in vivo" e "in vitro" observadas nos animais wyld type diabéticos, mostrando que a ausência crônica dos receptores TRPV4 desencadeia alterações miccionais que são anteriores as causadas pelo diabetes. Também verificamos que os animais TRPM8-/- não apresentam alteração na resposta contrátil ao carbacol e à estimulação elétrica. Por outro lado, o mentol, mas não a icilina, reduziu significativamente as respostas contráteis nestes animais. O mentol inibiu o influxo de cálcio extracelular em cultura de células da musculatura lisa da bexiga por mecanismo inibitório direto nos canais Cav1.2. O tratamento agudo com mentol, intraperitoneal e intravesical, atenuou as disfunções miccionais observadas nos camundongos diabéticos. "In vitro" o pré-tratamento com mentol reduziu a hipercontratilidade ao carbacol no grupo diabético, sem alterar a resposta no grupo controle. Concluímos que o mentol impede a resposta contrátil da bexiga por mecanismo independente do receptor TRPM8 bloqueando o influxo de cálcio extracelular nos canais Cav1,2, podendo ser utilizado como tratamento na hiperatividade de bexiga de origem miogênica
Abstract: The TRPV4 and TRPM8 receptors are expressed in bladder urothelium and sensitive afferent fibers. Physiologically, the mechanical activation of TRPV4 receptor in the bladder wall is involved in micturition control. In inflammatory diseases, these receptors may have important roles. The bladder dysfunction in diabetes may be associated with changes at the level of detrusor, innervation and urothelium. The urothelial dysfunction triggers neural changes, modifying consequently the smooth muscle contractility. Thus, the goal of the present study was to investigate the pathophysiological mechanisms of TRPV4 and TRPM8 receptor activation in physiological and diabetic conditions in mice. For this purpose we divided the study in two phases, the first of which we evaluated the participation of TRPV4 and TRPM8 receptors in detrusor contractile and relaxing mechanisms in control and knockout animals for these channels. In the second phase we studied the activation of these channels in diabetic mice induced by intraperitoneal injection of streptozotocin (STZ; 180 mg / kg, 4 weeks). The TRPV4 agonist GSK1016790A produced concentration-dependent detrusor contractions. On the other hand, in detrusor pré-contracted with KCl (80 mM), GSK1016790A caused relaxation responses. In TRPV4-/- animals, we verified hypercontractility to carbachol (muscarinic agonist) and electrical-field stimulation, as well as a decreased relaxation to isoprenaline (non-selective ?-adrenergic agonist). These effects were not obtained with the TRPV4 antagonists, RN1734 and HC067047. Induction of diabetes with STZ caused hyperglycemia, mechanical nocicepton, and increased ratio between bladder and body weight after 4 weeks. The miccturition evaluationin diabetic animals showed increased capacity, urinary frequency, and non-voiding contractions. Hypercontractility to carbachol, electrical-field stimulation and KCl in isolated detrusor were lso observed. The induction of diabetes in TRPV4-/- animals did not change the urinary dysfunctions. Our data are consistent with the proposal that TRPV4 receptor has a physiological function in micturition control by decreasing muscarinic-induced contractions and increasing ?-adrenergic-mediated relaxations. Moreover, the bladder contractions to carbachol and EFS in TRPM8-/- did not significantly change compared to TRPM8+/+. However, menthol (300 ?M), but not icilin (1 ?M), significantly inhibited these contractile responses. The menthol (300 ?M) inhibited extracellular calcium influx in bladder smooth muscle cell culture by direct mechanism though Cav1.2 channels. In addition the acute treatment with menthol, intraperitoneal and intravesical, atenuated the micturition dysfunctions observed in diabetic mice. Also, detrusor preparations pre-treated with menthol decreased carbachol hypercontractility, without changing the responses in normoglycemic group. Menthol reduces bladder contractions by mechanisms independent of TRPM8 receptor activation, inhibiting extracellular calcium influx through Cav1.2 channel, thus been considered as treatment for bladder overactivity of myogenic origin
Doutorado
Farmacologia
Doutor em Farmacologia
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Chen, Wenchun [Verfasser], and Bernhard [Gutachter] Nieswandt. "Studies on the role of calcium channels and the kinase domain of transient receptor potential melastatin-like 7 (TRPM7) in platelet function / Wenchun Chen. Gutachter: Bernhard Nieswandt." Würzburg : Universität Würzburg, 2014. http://d-nb.info/1111783284/34.
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Gambade, Audrey. "Rôle du peptide LL-37 dans le cancer du sein : son interaction avec la membrane plasmique stimule l'entrée de calcium et la migration cellulaire par l'activation des canaux ioniques TRPV2 et BKCa." Thesis, Tours, 2015. http://www.theses.fr/2015TOUR3312/document.
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Le peptide antimicrobien LL-37 a été retrouvé surexprimé dans différents types de cancer et plus particulièrement dans le cancer du sein dans lequel il est associé au développement des métastases. Nous avons observé, in vitro, que la migration de trois lignées cancéreuses mammaires est augmentée par le peptide LL-37 et son énantiomère (D)-LL-37, excluant la fixation du peptide à un récepteur protéique. Sur les cellules cancéreuses mammaires MDA-MB-435s, le peptide se fixe à la membrane plasmique et diminue sa fluidité. La microscopie électronique localise LL-37 dans les cavéoles et à la surface de structures impliquées dans la migration cellulaire, les pseudopodes. LL-37 induit une entrée de calcium via le canal TRPV2 dont l’activité est augmentée par son recrutement dans les pseudopodes. Ce recrutement est dépendant de l’activation de la voie de signalisation PI3K/AKT induite par LL-37. L’entrée de calcium via TRPV2 est potentialisée par l’activation du canal potassique BKCa, localisé aussi dans les pseudopodes. Des ARN interférents contre TRPV2 inhibent à 70% la migration induite par LL-37, donnant un rôle prépondérant à ce canal dans les effets pro-migratoire du peptide. La fixation du peptide LL-37 aux membranes des cellules cancéreuses et l’activation de canaux ioniques constituent un nouvel axe de recherche pour comprendre le rôle du peptide dans la progression tumoraleThe antimicrobial peptide LL-37 is overexpressed in several types of cancer, among which breast cancer were it is associated with metastasis development. Our experiments on three mammary cancer cell lines have shown that LL-37 increases cell migration. Both its natural (L)-form and its (D)-enantiomer are equally active, excluding a specific binding to a protein receptor. On the MDA-MB-435s cell line, LL-37 attaches to plasma membrane and reduces its fluidity. Electron microscopy localized LL-37 on the surface of pseudopodia, structures implicated in cell migration, and in caveolae. LL-37 induces calcium entry via the TRPV2 channel, which is recruited to pseudopodia. Recruitment depends on activation of PI3K/AKT signaling induced by LL-37. Calcium entry via TRPV2 is potentiated by activation of the BKCa potassium channel also located in pseudopodia. TRPV2 suppression by RNA interference results in 70% reduction of cell migration induced by LL-37, attributing a crucial role of this channel to the promigratory effects of the peptide. Binding of LL-37 to cancer cell membranes and in consequence the activation of ion channels constitutes a novel research field to understand its role in tumor progression
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Shamsaldeen, Yousif. "Endothelial TRPV4 dysfunction in a streptozotocin-diabetic Rat Model." Thesis, University of Hertfordshire, 2016. http://hdl.handle.net/2299/17622.
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Diabetes mellitus is a complex disease characterised by chronic hyperglycaemia due to compromised insulin synthesis and secretion, or decreased tissue sensitivity to insulin, if not all three conditions. Endothelial dysfunction is a common complication in diabetes in which endothelium-dependent vasodilation is impaired. The aim of this study was to examine the involvement of TRPV4 in diabetes endothelial dysfunction. Male Charles River Wistar rats (350-450 g) were injected with 65mg/kg streptozotocin (STZ) intraperitoneally. STZ-injected rats were compared with naïve rats (not injected with STZ) or control rats (injected with 10ml/kg of 20mM citrate buffer, pH 4.0-4.5), if not both. Rats with blood glucose concentrations greater than 16mmol/L were considered to be diabetic. As the results revealed, STZ-diabetic rats showed significant endothelial dysfunction characterised by impaired muscarinic-induced vasodilation, as well as significant impairment in TRPV4-induced vasodilation in aortic rings and mesenteric arteries. Furthermore, STZ-diabetic primary aortic endothelial cells (ECs) showed a significant reduction in TRPV4-induced intracellular calcium ([Ca2+]i) elevation. TRPV4, endothelial nitric oxide synthase (eNOS), and caveolin-1 (CAV-1) were also significantly downregulated in STZ-diabetic primary aortic ECs and were later significantly restored by in vitro insulin treatment. Methylglyoxal (MGO) was significantly elevated in STZ-diabetic rat serum, and nondiabetic aortic rings incubated with MGO (100μM) for 12 hours showed significant endothelial dysfunction. Moreover, nondiabetic primary aortic ECs treated with MGO (100μM) for 5 days showed significant TRPV4 downregulation and significant suppression of 4-α-PDD-induced [Ca2+]i elevation, which was later restored by L-arginine (100μM) co-incubation. Incubating nondiabetic aortic rings with MGO (100μM) for 2 hours induced a spontaneous loss of noradrenaline-induced contractility persistence. Moreover, MGO induced significant [Ca2+]i elevation in Chinese hamster ovary cells expressing rat TRPM8 channels (rTRPM8), which was significantly inhibited by AMTB (1-5μM). Taken together, TRPV4, CAV-1, and eNOS can form a functional complex that is downregulated in STZ-diabetic aortic ECs and restored by insulin treatment. MGO elevation might furthermore contribute to diabetes endothelial dysfunction and TRPV4 downregulation. By contrast, MGO induced the loss of contractility persistence, possibly due to MGO's acting as a TRPM8 agonist.
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Lange, Ingo [Verfasser]. "The TRPM2 ion channel in nucleotide gated calcium signaling / vorgelegt von Ingo Lange." 2008. http://d-nb.info/989951200/34.
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Ehsan, Kheradpezhouh. "The role of TRPM2 channels in oxidative stress-induced liver damage." Thesis, 2015. http://hdl.handle.net/2440/92813.
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The increased production of highly reactive oxygen and nitrogen species plays a significant role in development of a number of liver disorders associated with hepatocellular death and impaired cell regeneration. Liver injury induced by drug toxicity, ischemia-reperfusion, excessive alcohol consumption and different types of viral hepatitis is in large part mediated by oxidative stress. Liver damage due to oxidative stress induced by drugs, including acetaminophen, accounts for 5% of all hospital admissions and for almost half of all acute liver failures. One of the features of hepatocellular death mediated by oxidative stress is Ca²⁺ overload due its release from intracellular organelles and activation of ion channels on the plasma membrane. Ca²⁺ is fundamental for normal cellular functioning. Ca²⁺ signalling, mediated by the rise in free cytoplasmic Ca²⁺ concentration ([Ca²⁺]c)[c subscript], regulates many cellular events. However, a sustained rise in [Ca²⁺]c [c subscript] can be detrimental, leading to mitochondrial dysfunction and cell death through apoptosis and necrosis. Although it is well recognised that Ca²⁺ plays a significant role in oxidative stress-induced liver damage, the molecular identities of the ion channels that provide a pathway for Ca²⁺ entry in hepatocytes remain unidentified. One of the potential candidates that could be responsible for such Ca²⁺ entry pathway in hepatocytes is Transient Receptor Potential Melastatin 2 (TRPM2) channel. TRPM2 is a non-selective cation channel permeable to Na⁺ and Ca²⁺. The main physiological activator of TRPM2 channel is ADP-ribose, which binding to NUDT9-H motif in the TRPM2 C-terminus leads to the opening of the channel pore. It is known that oxidative stress promotes generation and release of ADPR from mitochondria and nuclei into the cytoplasmic space, thus promoting activation of TRPM2-mediated Ca²⁺ entry. In this thesis, we hypothesised that oxidative stress-induced Ca²⁺ entry in hepatocytes is mediated by TRPM2 channels, and used acetaminophen overdose as a model of oxidative stress-induced liver damage. We show that hepatocytes express long isoform of TRPM2, which mediates ADPR- and H₂O₂-induced Ca²⁺ entry and the cation current in these cells. Furthermore, we show that TRPM2 channels are activated in hepatocytes treated with high concentrations of acetaminophen and are responsible for Ca²⁺ overload in acetaminophen-induced liver toxicity. Experiments using TRPM2 KO mice provide first evidence of a pivotal role of TRPM2 channels in acetaminophen-induced liver injury, showing that lack of TRPM2 expression largely protects liver from acetaminophen overdose. An important finding that TRPM2 channels translocate from intracellular compartments to the plasma membrane provides explanation for a slow development of Ca²⁺ entry in response to H₂O₂ and acetaminophen. Finally, we show that substances previously known to protect liver from acetaminophen-induced damage are, in fact, inhibitors of TRPM2 current. Chlorpromazine, an antipsychotic drug, reversibly blocks TRPM2 channel pore, and curcumin, a chemical found in common spice, potently blocks activation of TRPM2 current by ADPR. The results presented in this thesis provide a fundamental knowledge about the role of TRPM2 channels in oxidative stress-induced liver injury, but also open a new chapter in search for the new drugs and drug targets for the treatment of a number of oxidative stress-related liver pathologies.Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2015
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Roy, Jeremy. "THE CONTRIBUTION OF K+ ION CHANNELS AND THE Ca2+-PERMEABLE TRPM8 CHANNEL TO BREAST CANCER CELL PROLIFERATION." 2010. http://hdl.handle.net/10222/13118.
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Breast cancer is the most prevalent cancer type among Canadian women. Breast cancers originate from the malignant transformation of mammary epithelial cells, which causes them to adopt an uncontrolled cell proliferation phenotype.
My research suggests that the activity of specific ion channels (KV10.1, KCa3.1 and TRPM8) contribute to the proliferation of MCF-7 cells, a cell line commonly used to study breast cancer in vitro. Pharmacologically inhibiting the activities of KV10.1 or KCa3.1 channels decreased basal, but not estrogen-stimulated [3H]-thymidine incorporation, demonstrating that these channels contribute to MCF-7 cell proliferation. One way K+ channel activity is hypothesized to control cell proliferation is via regulation of membrane potential-dependent Ca2+ influx. Inhibition of KCa3.1 but not KV10.1 channel activity resulted in a membrane potential-dependent decrease in basal Ca2+ influx, suggesting that the way in which KCa3.1 channels contribute to cell proliferation is via regulating Ca2+ influx.
In addition, my research also demonstrated that TRAM-34 increased or decreased cell proliferation depending on the concentration used and mitogenesis by TRAM-34 was blocked by estrogen receptor antagonists. TRAM-34 increased progesterone receptor mRNA expression, decreased estrogen receptor-alpha mRNA expression and reduced the binding of radiolabelled estrogen to estrogen receptor protein, in each case mimicking the effects of estrogen. Our finding that TRAM-34 is able to activate the estrogen receptor suggests a novel action of this supposedly specific K+ channel inhibitor and raises concerns of interpretation in its use.
TRPM8 channels were also identified in MCF-7 cells, where they appeared to be important Ca2+ entry pathways. Inhibiting the activity of TRPM8 pharmacologically, as well as knocking down TRPM8 mRNA expression decreased cell proliferation, indicating that TRPM8 also contributed to MCF-7 cell proliferation.
In conclusion, my research demonstrates that the activities of KV10.1, KCa3.1 and TRPM8 channels contribute to basal breast cancer cell proliferation. These findings suggest that the activity of specific ion channels may be potential targets for future therapeutic agents to treat breast cancer.