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https://www.readbyqxmd.com/read/29617457/sur1-trpm4-channel-activation-and-phasic-secretion-of-mmp-9-induced-by-tpa-in-brain-endothelial-cells
#1
Volodymyr Gerzanich, Min Seong Kwon, Seung Kyoon Woo, Alexander Ivanov, J Marc Simard
BACKGROUND: Hemorrhagic transformation is a major complication of ischemic stroke, is linked to matrix metalloproteinase-9 (MMP-9), and is exacerbated by tissue plasminogen activator (tPA). Cerebral ischemia/reperfusion is characterized by SUR1-TRPM4 (sulfonylurea receptor 1-transient receptor potential melastatin 4) channel upregulation in microvascular endothelium. In humans and rodents with cerebral ischemia/reperfusion (I/R), the SUR1 antagonist, glibenclamide, reduces hemorrhagic transformation and plasma MMP-9, but the mechanism is unknown...
2018: PloS One
https://www.readbyqxmd.com/read/29579323/identification-of-potent-and-selective-small-molecule-inhibitors-of-the-cation-channel-trpm4
#2
Lijo Cherian Ozhathil, Clémence Delalande, Beatrice Bianchi, Gabor Nemeth, Sven Kappel, Urs Thomet, Daniela Ross-Kaschitza, Céline Simonin, Matthias Rubin, Jürg Gertsch, Martin Lochner, Christine Peinelt, Jean-Louis Reymond, Hugues Abriel
BACKGROUND AND PURPOSE: TRPM4 is a calcium-activated nonselective cation channel expressed in many tissues and implicated in several diseases, and has not yet been validated as a therapeutic target due to the lack of potent and selective inhibitors. We sought to discover a novel series of small-molecule inhibitor by combining in silico methods and cell based screening assay, with sub-micromolar potency and improved selectivity from previously reported TRPM4 inhibitors. EXPERIMENTAL APPROACH: Here, we developed a HTS compatible assay to record TRPM4-mediated Na+ influx in cells using a Na+ -sensitive dye and used this assay to screen a small set of compounds selected by ligand-based virtual screening using previously known weakly active and non-selective TRPM4 inhibitors as seed molecules...
March 26, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29569041/non-invasive-multimodality-imaging-directly-shows-trpm4-inhibition-ameliorates-stroke-reperfusion-injury
#3
Bo Chen, Gandi Ng, Yahui Gao, See Wee Low, Edwin Sandanaraj, Boominathan Ramasamy, Sakthivel Sekar, Kishore Bhakoo, Tuck Wah Soong, Bernd Nilius, Carol Tang, Edward G Robins, Julian Goggi, Ping Liao
The transient receptor potential melastatin 4 (TRPM4) channel has been suggested to play a key role in the treatment of ischemic stroke. However, in vivo evaluation of TRPM4 channel, in particular by direct channel suppression, is lacking. In this study, we used multimodal imaging to assess edema formation and quantify the amount of metabolically functional brain salvaged after a rat model of stroke reperfusion. TRPM4 upregulation in endothelium emerges as early as 2 h post-stroke induction. Expression of TRPM4 channel was suppressed directly in vivo by treatment with siRNA; scrambled siRNA was used as a control...
March 22, 2018: Translational Stroke Research
https://www.readbyqxmd.com/read/29568272/four-trpm4-cation-channel-mutations-found-in-cardiac-conduction-diseases-lead-to-altered-protein-stability
#4
Beatrice Bianchi, Lijo Cherian Ozhathil, Argelia Medeiros-Domingo, Michael H Gollob, Hugues Abriel
Transient receptor potential melastatin member 4 (TRPM4), a non-selective cation channel, mediates cell membrane depolarization in immune response, insulin secretion, neurological disorders, and cancer. Pathological variants in TRPM4 gene have been linked to several cardiac phenotypes such as complete heart block (CHB), ventricular tachycardia, and Brugada syndrome (BrS). Despite recent findings regarding the functional implications of TRPM4 in cardiac diseases, the molecular and cellular mechanisms leading to altered conduction are poorly understood...
2018: Frontiers in Physiology
https://www.readbyqxmd.com/read/29463718/structure-of-full-length-human-trpm4
#5
Jingjing Duan, Zongli Li, Jian Li, Ana Santa-Cruz, Silvia Sanchez-Martinez, Jin Zhang, David E Clapham
Transient receptor potential melastatin subfamily member 4 (TRPM4) is a widely distributed, calcium-activated, monovalent-selective cation channel. Mutations in human TRPM4 (hTRPM4) result in progressive familial heart block. Here, we report the electron cryomicroscopy structure of hTRPM4 in a closed, Na+ -bound, apo state at pH 7.5 to an overall resolution of 3.7 Å. Five partially hydrated sodium ions are proposed to occupy the center of the conduction pore and the entrance to the coiled-coil domain. We identify an upper gate in the selectivity filter and a lower gate at the entrance to the cytoplasmic coiled-coil domain...
February 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29440991/subcellular-localization-and-activity-of-trpm4-in-medial-prefrontal-cortex-layer-2-3
#6
Denise Riquelme, Ian Silva, Ashleigh M Philp, Juan P Huidobro-Toro, Oscar Cerda, James S Trimmer, Elias Leiva-Salcedo
TRPM4 is a Ca2+-activated non-selective cationic channel that conducts monovalent cations. TRPM4 has been proposed to contribute to burst firing and sustained activity in several brain regions, however, the cellular and subcellular pattern of TRPM4 expression in medial prefrontal cortex (mPFC) during postnatal development has not been elucidated. Here, we use multiplex immunofluorescence labeling of brain sections to characterize the postnatal developmental expression of TRPM4 in the mouse mPFC. We also performed electrophysiological recordings to correlate the expression of TRPM4 immunoreactivity with the presence of TRPM4-like currents...
2018: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29435486/transient-receptor-potential-channels-trpm4-and-trpc3-critically-contribute-to-respiratory-motor-pattern-formation-but-not-rhythmogenesis-in-rodent-brainstem-circuits
#7
Hidehiko Koizumi, Tibin T John, Justine X Chia, Mohammad F Tariq, Ryan S Phillips, Bryan Mosher, Yonghua Chen, Ryan Thompson, Ruli Zhang, Naohiro Koshiya, Jeffrey C Smith
Transient receptor potential channel, TRPM4, the putative molecular substrate for Ca2+-activated nonselective cation current (ICAN), is hypothesized to generate bursting activity of pre-Bötzinger complex (pre-BötC) inspiratory neurons and critically contribute to respiratory rhythmogenesis. Another TRP channel, TRPC3, which mediates Na+/Ca2+ fluxes, may be involved in regulating Ca2+-related signaling, including affecting TRPM4/ICAN in respiratory pre-BötC neurons. However, TRPM4 and TRPC3 expression in pre-BötC inspiratory neurons and functional roles of these channels remain to be determined...
January 2018: ENeuro
https://www.readbyqxmd.com/read/29390943/trpm4-induces-astrocyte-swelling-but-not-death-after-diffuse-traumatic-brain-injury
#8
Karen Gorse, Mary Kate Lantzy, Eun D Lee, Audrey D Lafrenaye
Traumatic brain injury (TBI) is a prevalent disease with significant costs. Although progress has been made in understanding the complex pathobiology of focal lesions associated with TBI, questions remain regarding the diffuse responses to injury. Expression of the transient receptor potential melastatin 4 (Trpm4) channel, is linked to cytotoxic edema during hemorrhagic contusion expansion. However, little is known about Trpm4 following diffuse TBI. To explore Trpm4 expression in diffuse TBI, rats were subjected to a diffuse central fluid percussion injury (CFPI) and survived for 1...
February 1, 2018: Journal of Neurotrauma
https://www.readbyqxmd.com/read/29311301/trpm4-and-trpm5-are-both-required-for-normal-signaling-in-taste-receptor-cells
#9
Debarghya Dutta Banik, Laura E Martin, Marc Freichel, Ann-Marie Torregrossa, Kathryn F Medler
Peripheral taste receptor cells use multiple signaling pathways to transduce taste stimuli into output signals that are sent to the brain. Transient receptor potential melastatin 5 (TRPM5), a sodium-selective TRP channel, functions as a common downstream component in sweet, bitter, and umami signaling pathways. In the absence of TRPM5, mice have a reduced, but not abolished, ability to detect stimuli, suggesting that a TRPM5-independent pathway also contributes to these signals. Here, we identify a critical role for the sodium-selective TRP channel TRPM4 in taste transduction...
January 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29240297/shared-cam-and-s100a1-binding-epitopes-in-the-distal-trpm4-n-terminus
#10
Kristyna Bousova, Petr Herman, Jaroslav Vecer, Lucie Bednarova, Lenka Monincova, Pavel Majer, Ladislav Vyklicky, Jiri Vondrasek, Jan Teisinger
The transient receptor potential channel of melastatin 4 (TRPM4) belongs to a group of large ion receptors that are involved in countless cell signalling cascades. This unique member is ubiquitously expressed in many human tissues, especially in cardiomyocytes, where it plays an important role in cardiovascular processes. Transient receptor potential channels (TRPs) are usually constituted by intracellular N- and C- termini, which serve as mediators affecting allosteric modulation of channels, resulting in the regulation of the channel function...
February 2018: FEBS Journal
https://www.readbyqxmd.com/read/29217581/structure-of-the-human-trpm4-ion-channel-in-a-lipid-nanodisc
#11
Henriette E Autzen, Alexander G Myasnikov, Melody G Campbell, Daniel Asarnow, David Julius, Yifan Cheng
Transient receptor potential (TRP) melastatin 4 (TRPM4) is a widely expressed cation channel associated with a variety of cardiovascular disorders. TRPM4 is activated by increased intracellular calcium in a voltage-dependent manner but, unlike many other TRP channels, is permeable to monovalent cations only. Here we present two structures of full-length human TRPM4 embedded in lipid nanodiscs at ~3-angstrom resolution, as determined by single-particle cryo-electron microscopy. These structures, with and without calcium bound, reveal a general architecture for this major subfamily of TRP channels and a well-defined calcium-binding site within the intracellular side of the S1-S4 domain...
January 12, 2018: Science
https://www.readbyqxmd.com/read/29211723/electron-cryo-microscopy-structure-of-a-human-trpm4-channel
#12
Paige A Winkler, Yihe Huang, Weinan Sun, Juan Du, Wei Lü
Ca2+ -activated, non-selective (CAN) ion channels sense increases of the intracellular Ca2+ concentration, producing a flux of Na+ and/or K+ ions that depolarizes the cell, thus modulating cellular Ca2+ entry. CAN channels are involved in cellular responses such as neuronal bursting activity and cardiac rhythm. Here we report the electron cryo-microscopy structure of the most widespread CAN channel, human TRPM4, bound to the agonist Ca2+ and the modulator decavanadate. Four cytosolic C-terminal domains form an umbrella-like structure with a coiled-coil domain for the 'pole' and four helical 'ribs' spanning the N-terminal TRPM homology regions (MHRs), thus holding four subunits in a crown-like architecture...
December 14, 2017: Nature
https://www.readbyqxmd.com/read/29211714/structures-of-the-calcium-activated-non-selective-cation-channel-trpm4
#13
Jiangtao Guo, Ji She, Weizhong Zeng, Qingfeng Chen, Xiao-Chen Bai, Youxing Jiang
TRPM4 is a calcium-activated, phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2 ) -modulated, non-selective cation channel that belongs to the family of melastatin-related transient receptor potential (TRPM) channels. Here we present the electron cryo-microscopy structures of the mouse TRPM4 channel with and without ATP. TRPM4 consists of multiple transmembrane and cytosolic domains, which assemble into a three-tiered architecture. The N-terminal nucleotide-binding domain and the C-terminal coiled-coil participate in the tetrameric assembly of the channel; ATP binds at the nucleotide-binding domain and inhibits channel activity...
December 14, 2017: Nature
https://www.readbyqxmd.com/read/29165759/transient-receptor-potential-melastatin-4-cation-channel-in-pediatric-heart-block
#14
J Tian, X-J An, M-Y Fu
Progressive cardiac conduction disease (PCCD) is a common pediatric heart conduction disorder. It is an autosomal inheritance of rare mutations, which leads to familial cases of PCCD. In these cases, the His-Purkinje system's conductive capacity is progressively deranged, involving either right or left bundle branch block. Also, QRS complexes display widening is an important characteristic that culminates in complete AV block, syncope, and sudden death. Mutations in TRPM4 gene that encodes for transient receptor potential melastatin 4 have recently been reported to cause familial cases of PCCD and heart block...
October 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/29150777/glibenclamide-and-therapeutic-hypothermia-have-comparable-effect-on-attenuating-global-cerebral-edema-following-experimental-cardiac-arrest
#15
Shin Nakayama, Noriko Taguchi, Yumi Isaka, Takako Nakamura, Makoto Tanaka
BACKGROUND: Cerebral edema is one of the major causes of mortality following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). A subunit of the sulfonylurea receptor 1-transient receptor potential M4 (Sur1-TRPM4) channel has been implicated in the pathogenesis of ischemia-evoked cerebral edema. In this study, we examined whether glibenclamide (GBC), a Sur1-TRPM4 channel inhibitor, attenuates cerebral edema following CA/CPR and further examined the efficacy of GBC combined with therapeutic hypothermia...
November 17, 2017: Neurocritical Care
https://www.readbyqxmd.com/read/29098165/a-trpm4-inhibitor-9-phenanthrol-inhibits-glucose-and-glucagon-like-peptide-1-induced-insulin-secretion-from-rat-islets-of-langerhans
#16
Zuheng Ma, Anneli Björklund, Md Shahidul Islam
Pancreatic β -cells express several ion channels of the transient receptor potential family, which play important roles in mediating the stimulus-secretion coupling. One of these channels, the TRPM4 is a Ca2+ -activated monovalent cation channel. This channel is inhibited by 9-phenanthrol, which also inhibits the TMEM16a Cl- channel, and activates the Ca2+ -activated K+ channel, Kca 3.1. The net effects of ion-channel modulation by 9-phenantherol on the insulin secretion remain unclear. We tested the effects of 9-phenanthrol on glucose- and GLP-1-induced insulin secretion from isolated rat islets in static incubations...
2017: Journal of Diabetes Research
https://www.readbyqxmd.com/read/29095086/trpm4-and-the-emperor
#17
J Marc Simard, Volodymyr Gerzanich
No abstract text is available yet for this article.
November 2, 2017: Channels
https://www.readbyqxmd.com/read/29052994/force-induced-calpain-cleavage-of-talin-is-critical-for-growth-adhesion-development-and-rigidity-sensing
#18
Mayur Saxena, Rishita Changede, James Hone, Haguy Wolfenson, Michael P Sheetz
Cell growth depends upon formation of cell-matrix adhesions, but mechanisms detailing the transmission of signals from adhesions to control proliferation are still lacking. Here, we find that the scaffold protein talin undergoes force-induced cleavage in early adhesions to produce the talin rod fragment that is needed for cell cycle progression. Expression of noncleavable talin blocks cell growth, adhesion maturation, proper mechanosensing, and the related property of EGF activation of motility. Further, the expression of talin rod in the presence of noncleavable full-length talin rescues cell growth and other functions...
December 13, 2017: Nano Letters
https://www.readbyqxmd.com/read/29048243/mithramycin-a-improves-functional-recovery-by-inhibiting-bscb-disruption-and-hemorrhage-after-spinal-cord-injury
#19
Jee Y Lee, Hae Y Choi, Chan S Park, Bong G Ju, Tae Y Yune
After spinal cord injury (SCI), blood-spinal cord barrier (BSCB) disruption and progressive hemorrhage lead to secondary injury, subsequent apoptosis and/or necrosis of neurons and glia, causing permanent neurological deficits. Growing evidence indicates that mithramycin A (MA), an anti-cancer drug, has neuroprotective effects in ischemic brain injury and Huntington's disease (HD). However, the precise mechanism underlying its protective effects is largely unknown. Here, we examined the effect of MA on BSCB breakdown and hemorrhage as well as subsequent inflammation after SCI...
November 17, 2017: Journal of Neurotrauma
https://www.readbyqxmd.com/read/29019677/scalaradial-is-a-potent-inhibitor-of-transient-receptor-potential-melastatin-2-trpm2-ion-channels
#20
John G Starkus, Peter Poerzgen, Kristine Layugan, Kelly Galbraith Kawabata, Jun-Ichi Goto, Sayuri Suzuki, George Myers, Michelle Kelly, Reinhold Penner, Andrea Fleig, F David Horgen
TRPM2 is a Ca2+ -permeable, nonselective cation channel that plays a role in oxidant-induced cell death, insulin secretion, and cytokine release. Few TRPM2 inhibitors have been reported, which hampers the validation of TRPM2 as a drug target. While screening our in-house marine-derived chemical library, we identified scalaradial and 12-deacetylscalaradial as the active components within an extract of an undescribed species of Cacospongia (class Demospongiae, family Thorectidae) that strongly inhibited TRPM2-mediated Ca2+ influx in TRPM2-overexpressing HEK293 cells...
October 27, 2017: Journal of Natural Products
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