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Sonya Marshall-Gradisnik, Samantha Johnston, Anu Chacko, Thao Nguyen, Peter Smith, Donald Staines
OBJECTIVE: The pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is unknown; however, a small subgroup of patients has shown muscarinic antibody positivity and reduced symptom presentation following anti-CD20 intervention. Given the important roles of calcium (Ca(2+)) and acetylcholine (ACh) signalling in B cell activation and potential antibody development, we aimed to identify relevant single nucleotide polymorphisms (SNPs) and genotypes in isolated B cells from CFS/ME patients...
November 10, 2016: Journal of International Medical Research
Bing Jiang, Lin Li, Qianwei Chen, Yihao Tao, Liming Yang, Bo Zhang, John H Zhang, Hua Feng, Zhi Chen, Jun Tang, Gang Zhu
Brain edema following intracerebral hemorrhage (ICH) causes severe secondary brain injury, and no efficient pharmacological preventions are available. The present study was designed to demonstrate the neuroprotective effects of glibenclamide on brain edema and key factors of the blood-brain barrier (BBB). The study was divided into two parts. First, we utilized an autoblood-induced rat model to investigate the expression of sulfonylurea receptor 1 (Sur1). Second, rats were randomized into sham, vehicle, and glibenclamide groups...
November 3, 2016: Translational Stroke Research
Mary K McGahon, José A Fernández, Durga P Dash, Jon McKee, David A Simpson, Alex V Zholos, J Graham McGeown, Tim M Curtis
Purpose: Activation of the transient receptor potential channels, TRPC6, TRPM4, and TRPP1 (PKD2), has been shown to contribute to the myogenic constriction of cerebral arteries. In the present study we sought to determine the potential role of various mechanosensitive TRP channels to myogenic signaling in arterioles of the rat retina. Methods: Rat retinal arterioles were isolated for RT-PCR, Fura-2 Ca2+ microfluorimetry, patch-clamp electrophysiology, and pressure myography studies...
October 1, 2016: Investigative Ophthalmology & Visual Science
Torben Rixecker, Ilka Mathar, Rebekka Medert, Stefanie Mannebach, Alexander Pfeifer, Peter Lipp, Volodymyr Tsvilovskyy, Marc Freichel
TRPM4 proteins form Ca(2+)-activated non selective cation (CAN) channels that affect transmembrane Ca(2+)-influx by determining the membrane potential. Tight control of the intracellular Ca(2+) concentration is essential for mast cell responses. In this study, we analyzed the expression of TRPM4 in peritoneal mast cells (PCMC) as a model for connective tissue type mast cells with respect to FcεRI-evoked calcium changes and the subcellular localization of fluorescently labeled TRPM4 using two viral transduction systems before and following antigen stimulation...
2016: Scientific Reports
Francesco Marabita, Md Shahidul Islam
OBJECTIVE: Members of the transient receptor potential (TRP) channels are involved in mediating the electrical excitability and stimulus-secretion coupling in the pancreatic β-cells. The expression and the relative abundance of different TRP channels in the human β-cells are unknown. The objective of this study was to examine the expression of the TRP channels and their relative abundance in the human β-cell. METHODS: RNA sequencing data obtained from human islets, fluorescence-activated cell sorting-purified human β-cell and human pancreatic acinar cells were analyzed...
July 25, 2016: Pancreas
Kaibin Huang, Ziyue Wang, Yong Gu, Yafang Hu, Zhong Ji, Shengnan Wang, Zhenzhou Lin, Xing Li, Zuoshan Xie, Suyue Pan
BACKGROUND: We previously have shown that glibenclamide (GBC), a sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) channel inhibitor, improves survival and neurological outcome after asphyxial cardiac arrest and cardiopulmonary resuscitation (ACA/CPR). Here, we further compare the efficacy of GBC with target temperature management (TTM) and determine whether the efficacy of GBC is affected by TTM. METHODS AND RESULTS: Male Sprague-Dawley rats (n=213) subjected to 10-minute ACA/CPR were randomized to 4 groups after return of spontaneous circulation (ROSC): normothermia control (NT); GBC; TTM; and TTM+GBC...
July 13, 2016: Journal of the American Heart Association
Michael G Leitner, Niklas Michel, Marc Behrendt, Marlen Dierich, Sandeep Dembla, Bettina U Wilke, Maik Konrad, Moritz Lindner, Johannes Oberwinkler, Dominik Oliver
BACKGROUND AND PURPOSE: Signalling through phospholipase C (PLC) controls many cellular processes. Much information on the relevance of this important pathway has been derived from pharmacological inhibition of the enzymatic activity of PLC. We found that the most frequently employed PLC inhibitor, U73122, activates endogenous ionic currents in widely used cell lines. Given the extensive use of U73122 in research, we set out to identify these U73122-sensitive ion channels. EXPERIMENTAL APPROACH: We performed detailed biophysical analysis of the U73122-induced currents in frequently used cell lines...
August 2016: British Journal of Pharmacology
David B Kurland, Volodymyr Gerzanich, Jason K Karimy, Seung Kyoon Woo, Rudi Vennekens, Marc Freichel, Bernd Nilius, Joseph Bryan, J Marc Simard
BACKGROUND: Harmful effects of activated microglia are due, in part, to the formation of peroxynitrite radicals, which is attributable to the upregulation of inducible nitric oxide (NO) synthase (NOS2). Because NOS2 expression is determined by Ca(2+)-sensitive calcineurin (CN) dephosphorylating nuclear factor of activated T cells (NFAT), and because Sur1-Trpm4 channels are crucial for regulating Ca(2+) influx, we hypothesized that, in activated microglia, Sur1-Trpm4 channels play a central role in regulating CN/NFAT and downstream target genes such as Nos2...
June 1, 2016: Journal of Neuroinflammation
Ninda Syam, Stéphanie Chatel, Lijo Cherian Ozhathil, Valentin Sottas, Jean-Sébastien Rougier, Alban Baruteau, Estelle Baron, Mohamed-Yassine Amarouch, Xavier Daumy, Vincent Probst, Jean-Jacques Schott, Hugues Abriel
BACKGROUND: Transient receptor potential melastatin member 4 (TRPM4) is a nonselective cation channel. TRPM4 mutations have been linked to cardiac conduction disease and Brugada syndrome. The mechanisms underlying TRPM4-dependent conduction slowing are not fully understood. The aim of this study was to characterize TRPM4 genetic variants found in patients with congenital or childhood atrioventricular block. METHODS AND RESULTS: Ninety-one patients with congenital or childhood atrioventricular block were screened for candidate genes...
May 2016: Journal of the American Heart Association
Qian Wang, M Dennis Leo, Damodaran Narayanan, Korah P Kuruvilla, Jonathan H Jaggar
Anoctamin-1 [ANO1, also known as transmembrane protein 16A (TMEM16A)] is a Ca(2+)-activated Cl(-) channel expressed in arterial myocytes that regulates membrane potential and contractility. Signaling mechanisms that control ANO1 activity in arterial myocytes are poorly understood. In cerebral artery myocytes, ANO1 channels are activated by local Ca(2+) signals generated by plasma membrane nonselective cation channels, but the molecular identity of these proteins is unclear. Arterial myocytes express several different nonselective cation channels, including multiple members of the transient receptor potential receptor (TRP) family...
June 1, 2016: American Journal of Physiology. Cell Physiology
Liang He, Janne Pitkäniemi, Kauko Heikkilä, Yi-Ling Chou, Pamela A F Madden, Tellervo Korhonen, Antti-Pekka Sarin, Samuli Ripatti, Jaakko Kaprio, Anu Loukola
BACKGROUND: Various pivotal stages in smoking behavior can be identified, including initiation, conversion from experimenting to established use, development of tolerance, and cessation. Previous studies have shown high heritability for age of smoking initiation and cessation; however, time-to-event genome-wide association studies aiming to identify underpinning genes that accelerate or delay these transitions are missing to date. METHODS: We investigated which single nucleotide polymorphisms (SNPs) across the whole genome contribute to the hazard ratio of transition between different stages of smoking behavior by performing time-to-event analyses within a large Finnish twin family cohort (N = 1962), and further conducted mediation analyses of plausible intermediate traits for significant SNPs...
May 2016: Brain and Behavior
Xavier Daumy, Mohamed-Yassine Amarouch, Pierre Lindenbaum, Stéphanie Bonnaud, Eric Charpentier, Beatrice Bianchi, Sabine Nafzger, Estelle Baron, Swanny Fouchard, Aurélie Thollet, Florence Kyndt, Julien Barc, Solena Le Scouarnec, Naomasa Makita, Hervé Le Marec, Christian Dina, Jean-Baptiste Gourraud, Vincent Probst, Hugues Abriel, Richard Redon, Jean-Jacques Schott
BACKGROUND: Progressive cardiac conduction disease (PCCD) is one of the most common cardiac conduction disturbances. It has been causally related to rare mutations in several genes including SCN5A, SCN1B, TRPM4, LMNA and GJA5. METHODS AND RESULTS: In this study, by applying targeted next-generation sequencing (NGS) in 95 unrelated patients with PCCD, we have identified 13 rare variants in the TRPM4 gene, two of which are currently absent from public databases. This gene encodes a cardiac calcium-activated cationic channel which precise role and importance in cardiac conduction and disease is still debated...
March 15, 2016: International Journal of Cardiology
Kiril L Hristov, Amy C Smith, Shankar P Parajuli, John Malysz, Eric S Rovner, Georgi V Petkov
Transient receptor potential melastatin 4 (TRPM4) channels are Ca(2+)-activated nonselective cation channels that have been recently identified as regulators of detrusor smooth muscle (DSM) function in rodents. However, their expression and function in human DSM remain unexplored. We provide insights into the functional role of TRPM4 channels in human DSM under physiological conditions. We used a multidisciplinary experimental approach, including RT-PCR, Western blotting, immunohistochemistry and immunocytochemistry, patch-clamp electrophysiology, and functional studies of DSM contractility...
April 1, 2016: American Journal of Physiology. Cell Physiology
Maryrose Constantine, Chu Kong Liew, Victor Lo, Alex Macmillan, Charles G Cranfield, Margaret Sunde, Renee Whan, Robert M Graham, Boris Martinac
Mutation, irregular expression and sustained activation of the Transient Receptor Potential Channel, type Melastatin 4 (TRPM4), have been linked to various cardiovascular diseases. However, much remains unknown about the structure of this important ion channel. Here, we have purified a heterologously expressed TRPM4-eGFP fusion protein and investigated the oligomeric state of TRPM4-eGFP in detergent micelles using crosslinking, native gel electrophoresis, multi-angle laser light scattering and electron microscopy...
2016: Scientific Reports
Yao Li, Joseph E Brayden
Cerebral arterioles contribute critically to regulation of local and global blood flow within the brain. Dysfunction of these blood vessels is implicated in numerous cardiovascular diseases. However, treatments are limited due to incomplete understanding of fundamental control mechanisms at this level of circulation. Emerging evidence points to a key role of Rho-associated protein kinase in regulation of microvascular contractility. This study sought to decipher the mechanisms of Rho-associated protein kinase-mediated myogenic vasoconstriction in cerebral parenchymal arterioles...
December 7, 2015: Journal of Cerebral Blood Flow and Metabolism
Patrícia B S Celestino-Soper, Anisiia Doytchinova, Hillel A Steiner, Andrea Uradu, Ty C Lynnes, William J Groh, John M Miller, Hai Lin, Hongyu Gao, Zhiping Wang, Yunlong Liu, Peng-Sheng Chen, Matteo Vatta
BACKGROUND: The etiology of conduction disturbances necessitating permanent pacemaker (PPM) implantation is often unknown, although familial aggregation of PPM (faPPM) suggests a possible genetic basis. We developed a pan-cardiovascular next generation sequencing (NGS) panel to genetically characterize a selected cohort of faPPM. MATERIALS AND METHODS: We designed and validated a custom NGS panel targeting the coding and splicing regions of 246 genes with involvement in cardiac pathogenicity...
2015: PloS One
Aurélie Menigoz, Tariq Ahmed, Victor Sabanov, Koenraad Philippaert, Silvia Pinto, Sara Kerselaers, Andrei Segal, Marc Freichel, Thomas Voets, Bernd Nilius, Rudi Vennekens, Detlef Balschun
TRPM4 is a calcium-activated but calcium-impermeable non-selective cation (CAN) channel. Previous studies have shown that TRPM4 is an important regulator of Ca(2+)-dependent changes in membrane potential in excitable and non-excitable cell types. However, its physiological significance in neurons of the central nervous system remained unclear. Here, we report that TRPM4 proteins form a CAN channel in CA1 neurons of the hippocampus and we show that TRPM4 is an essential co-activator of N-methyl-D-aspartate (NMDA) receptors (NMDAR) during the induction of long-term potentiation (LTP)...
April 2016: Pflügers Archiv: European Journal of Physiology
Kasper Drimer Berg, Davide Soldini, Maria Jung, Dimo Dietrich, Carsten Stephan, Klaus Jung, Manfred Dietel, Ben Vainer, Glen Kristiansen
BACKGROUND: Transient receptor potential cation channel, subfamily M, member 4 (TRPM4) messenger RNA (mRNA) has been shown to be upregulated in prostate cancer (PCa) and might be a new promising tissue biomarker. We evaluated TRPM4 protein expression and correlated the expression level with biochemical recurrence (BR) following radical prostatectomy (RP). MATERIAL AND METHODS: The study included 614 patients who had undergone RP. TRPM4 immunohistochemical staining was performed on samples of benign tissue, tissue containing PIN glands and PCa tissue using a commercially available polyclonal antibody...
March 2016: Virchows Archiv: An International Journal of Pathology
Tapas K Makar, Volodymyr Gerzanich, Vamshi K C Nimmagadda, Rupal Jain, Kristal Lam, Fahad Mubariz, David Trisler, Svetlana Ivanova, Seung Kyoon Woo, Min Seong Kwon, Joseph Bryan, Christopher T Bever, J Marc Simard
BACKGROUND: In experimental autoimmune encephalomyelitis (EAE), deletion of transient receptor potential melastatin 4 (Trpm4) and administration of glibenclamide were found to ameliorate disease progression, prompting speculation that glibenclamide acts by directly inhibiting Trpm4. We hypothesized that in EAE, Trpm4 upregulation is accompanied by upregulation of sulfonylurea receptor 1 (Sur1) to form Sur1-Trpm4 channels, which are highly sensitive to glibenclamide, and that Sur1-Trpm4 channels are required for EAE progression...
November 18, 2015: Journal of Neuroinflammation
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