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Dong Kun Lee, Jung Yeon Park, Jae Cheal Yoo, Eun Hye Byun, Yeon-Ju Bae, Young-Sun Lee, Nammi Park, Dawon Kang, Jaehee Han, Jae Yong Park, Eunmi Hwang, Seong-Geun Hong
Transient receptor-potential, cation channel, subfamily M, member 4 (TRPM4) channels regulate a variety of physiological and pathological processes; however, their roles as functional channels under diverse conditions remain unclear. In this study, cytosolic protein tyrosine phosphatase non-receptor type 6 (PTPN6) interacted with TRPM4 channels. We confirmed their interaction by performing co-immunoprecipitation (Co-IP) assays following heterologous PTPN6 and TRPM4 channel expression in HEK293 cells. Furthermore, biomolecular fluorescence complementation (BiFC) image analysis confirmed TRPM4-PTPN6 binding...
June 21, 2018: Pflügers Archiv: European Journal of Physiology
Chen Wang, Keiji Naruse, Ken Takahashi
The transient receptor potential cation channel subfamily M member 4 (TRPM4) channel influences calcium homeostasis during many physiological activities such as insulin secretion, immune response, respiratory reaction, and cerebral vasoconstriction. This calcium-activated, monovalent, selective cation channel also plays a key role in cardiovascular pathophysiology; for example, a mutation in the TRPM4 channel leads to cardiac conduction disease. Recently, it has been suggested that the TRPM4 channel is also involved in the development of cardiac ischemia-reperfusion injury, which causes myocardial infarction...
June 15, 2018: Cells
Aline Hantute-Ghesquier, Aurélien Haustrate, Natalia Prevarskaya, V'yacheslav Lehen'kyi
Members of the TRPM ("Melastatin") family fall into the subclass of the TRP channels having varying permeability to Ca2+ and Mg2+ , with three members of the TRPM family being chanzymes, which contain C-terminal enzyme domains. The role of different TRPM members has been shown in various cancers such as prostate cancer for mostly TRPM8 and TRPM2, breast cancer for mostly TRPM2 and TRPM7, and pancreatic cancer for TRPM2/7/8 channels. The role of TRPM5 channels has been shown in lung cancer, TRPM1 in melanoma, and TRPM4 channel in prostate cancer as well...
June 7, 2018: Pharmaceuticals
Roland Veress, Dóra Baranyai, Bence Hegyi, Kornél Kistamás, Csaba Dienes, János Magyar, Tamás Bányász, Péter P Nánási, Norbert Szentandrássy, Balázs Horváth
The role of TRPM4 channels has been frequently tested using their inhibitor 9-phenanthrol in various cardiac preparations, however, the selectivity of the compound is uncertain. Therefore, in the present study the concentration-dependent effects of 9-phenanthrol on major ionic currents were studied in canine isolated ventricular cells using whole-cell configuration of the patch-clamp technique and 10 mM BAPTA-containing pipette solution in order to prevent the Ca2+-dependent activation of TRPM4 channels. Transient outward, rapid delayed rectifier and inward rectifier K+ currents were suppressed by 10 and 30 µM 9-phenanthrol with the blocking potency for IK1<IKr<Ito1 and partial reversibility...
May 28, 2018: Canadian Journal of Physiology and Pharmacology
Peidian Shi, Lilin Zhang, Jiashun Wang, Dong Lu, Yi Li, Jie Ren, Menglu Shen, Lei Zhang, Jinhai Huang
Porcine reproductive and respiratory syndrome virus (PRRSV) shows characteristic antibody-dependent enhancement (ADE) of infection and causes porcine systemic inflammation, which is similar to a type I allergic reaction; however, the role of porcine FcεRI in ADE is still unclear. In this study, the expression of different Fc receptors (FcRs) on macrophages was investigated in a PRRSV 3D4/21 cell infection model in the presence or absence of PRRSV antibody. The transcription level of FcγII and FcεRI was significantly up-regulated under PRRSV-antibody complex infection...
May 14, 2018: Virologica Sinica
Yukihiro Saito, Kazufumi Nakamura, Nobuhiro Nishi, Osamu Igawa, Masashi Yoshida, Toru Miyoshi, Atsuyuki Watanabe, Hiroshi Morita, Hiroshi Ito
No abstract text is available yet for this article.
May 2018: Circulation. Genomic and precision medicine
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
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 non-selective 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 inhibitors 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 high throughput screening 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
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
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
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...
March 6, 2018: Proceedings of the National Academy of Sciences of the United States of America
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
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 ( I CAN ), 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/ I CAN 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
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
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
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
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
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
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
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