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https://www.readbyqxmd.com/read/29217581/structure-of-the-human-trpm4-ion-channel-in-a-lipid-nanodisc
#1
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 ~3Å resolution as determined by single particle electron cryo-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...
December 7, 2017: Science
https://www.readbyqxmd.com/read/29211723/electron-cryo-microscopy-structure-of-a-human-trpm4-channel
#2
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 6, 2017: Nature
https://www.readbyqxmd.com/read/29211714/structures-of-the-calcium-activated-non-selective-cation-channel-trpm4
#3
Jiangtao Guo, Ji She, Weizhong Zeng, Qingfeng Chen, Youxing Jiang, Xiao-Chen Bai
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 6, 2017: Nature
https://www.readbyqxmd.com/read/29165759/transient-receptor-potential-melastatin-4-cation-channel-in-pediatric-heart-block
#4
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
#5
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
#6
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 Ca(2+)-activated monovalent cation channel. This channel is inhibited by 9-phenanthrol, which also inhibits the TMEM16a Cl(-) channel, and activates the Ca(2+)-activated K(+) channel, Kca3.1. 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
#7
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
#8
Mayur Saxena, Rishita Changede, James C 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 non-cleavable 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 non-cleavable full-length talin rescues cell growth and other functions...
October 20, 2017: Nano Letters
https://www.readbyqxmd.com/read/29048243/mithramycin-a-improves-functional-recovery-by-inhibiting-bscb-disruption-and-hemorrhage-after-spinal-cord-injury
#9
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
#10
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 Ca(2+)-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 Ca(2+) influx in TRPM2-overexpressing HEK293 cells...
October 27, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/28906027/sur1-trpm4-and-aqp4-form-a-heteromultimeric-complex-that-amplifies-ion-water-osmotic-coupling-and-drives-astrocyte-swelling
#11
Jesse A Stokum, Min S Kwon, Seung K Woo, Orest Tsymbalyuk, Rudi Vennekens, Volodymyr Gerzanich, J Marc Simard
Astrocyte swelling occurs after central nervous system injury and contributes to brain swelling, which can increase mortality. Mechanisms proffered to explain astrocyte swelling emphasize the importance of either aquaporin-4 (AQP4), an astrocyte water channel, or of Na(+) -permeable channels, which mediate cellular osmolyte influx. However, the spatio-temporal functional interactions between AQP4 and Na(+) -permeable channels that drive swelling are poorly understood. We hypothesized that astrocyte swelling after injury is linked to an interaction between AQP4 and Na(+) -permeable channels that are newly upregulated...
January 2018: Glia
https://www.readbyqxmd.com/read/28898995/uncovering-the-arrhythmogenic-potential-of-trpm4-activation-in-atrial-derived-hl-1-cells-using-novel-recording-and-numerical-approaches
#12
Yaopeng Hu, Yubin Duan, Ayako Takeuchi, Lin Hai-Kurahara, Jun Ichikawa, Keizo Hiraishi, Tomohiro Numata, Hiroki Ohara, Gentaro Iribe, Michio Nakaya, Masayuki X Mori, Satoshi Matsuoka, Genshan Ma, Ryuji Inoue
Aims: Transient receptor potential cation channel subfamily melastatin member 4 (TRPM4), a Ca2+-activated nonselective cation channel abundantly expressed in the heart, has been implicated in conduction block and other arrhythmic propensities associated with cardiac remodelling and injury. The present study aimed to quantitatively evaluate the arrhythmogenic potential of TRPM4. Methods and results: Patch clamp and biochemical analyses were performed using expression system and an immortalized atrial cardiomyocyte cell line (HL-1), and numerical model simulation was employed...
August 1, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28877214/direct-versus-indirect-actions-of-ghrelin-on-hypothalamic-npy-neurons
#13
Hiroshi Hashiguchi, Zhenyu Sheng, Vanessa Routh, Volodymyr Gerzanich, J Marc Simard, Joseph Bryan
OBJECTIVES: Assess direct versus indirect action(s) of ghrelin on hypothalamic NPY neurons. MATERIALS AND METHODS: Electrophysiology was used to measure ion channel activity in NPY-GFP neurons in slice preparations. Ca2+ imaging was used to monitor ghrelin activation of isolated NPY GFP-labeled neurons. Immunohistochemistry was used to localize Trpm4, SUR1 and Kir6.2 in the hypothalamus. RESULTS: Acylated ghrelin depolarized the membrane potential (MP) of NPY-GFP neurons in brain slices...
2017: PloS One
https://www.readbyqxmd.com/read/28876976/trpm4-activation-by-chemically-and-oxygen-deprivation-induced-ischemia-and-reperfusion-triggers-neuronal-death
#14
Elías Leiva-Salcedo, Denise Riquelme, Oscar Cerda, Andrés Stutzin
Cerebral ischemia-reperfusion injury triggers a deleterious process ending in neuronal death. This process has two components, a glutamate-dependent and a glutamate-independent mechanism. In the glutamate-independent mechanism, neurons undergo a slow depolarization eventually leading to neuronal death. However, little is known about the molecules that take part in this process. Here we show by using mice cortical neurons in culture and ischemia-reperfusion protocols that TRPM4 is fundamental for the glutamate-independent neuronal damage...
September 6, 2017: Channels
https://www.readbyqxmd.com/read/28865458/salutary-effects-of-glibenclamide-during-the-chronic-phase-of-murine-experimental-autoimmune-encephalomyelitis
#15
Volodymyr Gerzanich, Tapas K Makar, Poornachander Reddy Guda, Min Seong Kwon, Jesse A Stokum, Seung Kyoon Woo, Svetlana Ivanova, Alexander Ivanov, Rupal I Mehta, Alexandra Brooke Morris, Joseph Bryan, Christopher T Bever, J Marc Simard
BACKGROUND: In multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), inflammation is perpetuated by both infiltrating leukocytes and astrocytes. Recent work implicated SUR1-TRPM4 channels, expressed mostly by astrocytes, in murine EAE. We tested the hypothesis that pharmacological inhibition of SUR1 during the chronic phase of EAE would be beneficial. METHODS: EAE was induced in mice using myelin oligodendrocyte glycoprotein (MOG) 35-55. Glibenclamide (10 μg/day) was administered beginning 12 or 24 days later...
September 2, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28839241/leukocyte-trp-channel-gene-expressions-in%C3%A2-patients-with-non-valvular-atrial-fibrillation
#16
Irfan V Düzen, Fethi Yavuz, Ertan Vuruskan, Erhan Saracoglu, Fatih Poyraz, Hüseyin Göksülük, Basar Candemir, Seniz Demiryürek
Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is a major cause of morbidity and mortality. The upregulation of TRP channels is believed to mediate the progression of electrical remodelling and the arrhythmogenesis of the diseased heart. However, there is limited data about the contribution of the TRP channels to development of AF. The aim of this study was to investigate leukocyte TRP channels gene expressions in non-valvular atrial fibrillation (NVAF) patients. The study included 47 NVAF patients and 47 sex and age matched controls...
August 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28758259/transient-receptor-potential-melastatin-4-channel-is-required-for-rat-dental-pulp-stem-cell-proliferation-and-survival
#17
T D Ngoc Tran, K E Stovall, T Suantawee, Y Hu, S Yao, L-J Yang, S Adisakwattana, H Cheng
OBJECTIVES: Investigate the role of the transient receptor potential melastatin 4 (TRPM4) channel in rat dental pulp stem cell (DPSC) proliferation and survival. MATERIALS AND METHODS: Immunofluorescence and FACS analysis were used to detect the stem cell marker CD90. Alizarin Red S and Oil Red O staining were used to identify osteoblast and adipocyte differentiation, respectively. To characterize TRPM4, patch-clamp recordings were obtained from single cells in the whole-cell configuration mode...
October 2017: Cell Proliferation
https://www.readbyqxmd.com/read/28750076/targeted-next-generation-sequencing-detects-novel-gene-phenotype-associations-and-expands-the-mutational-spectrum-in-cardiomyopathies
#18
Cinzia Forleo, Anna Maria D'Erchia, Sandro Sorrentino, Caterina Manzari, Matteo Chiara, Massimo Iacoviello, Andrea Igoren Guaricci, Delia De Santis, Rita Leonarda Musci, Antonino La Spada, Vito Marangelli, Graziano Pesole, Stefano Favale
Cardiomyopathies are a heterogeneous group of primary diseases of the myocardium, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC), with higher morbidity and mortality. These diseases are genetically diverse and associated with rare mutations in a large number of genes, many of which overlap among the phenotypes. To better investigate the genetic overlap between these three phenotypes and to identify new genotype-phenotype correlations, we designed a custom gene panel consisting of 115 genes known to be associated with cardiomyopathic phenotypes and channelopathies...
2017: PloS One
https://www.readbyqxmd.com/read/28740332/a-protective-role-of-glibenclamide-in-inflammation-associated-injury
#19
REVIEW
Gensheng Zhang, Xiuhui Lin, Shufang Zhang, Huiqing Xiu, Chuli Pan, Wei Cui
Glibenclamide is the most widely used sulfonylurea drug for the treatment of type 2 diabetes mellitus (DM). Recent studies have suggested that glibenclamide reduced adverse neuroinflammation and improved behavioral outcomes following central nervous system (CNS) injury. We reviewed glibenclamide's anti-inflammatory effects: abundant evidences have shown that glibenclamide exerted an anti-inflammatory effect in respiratory, digestive, urological, cardiological, and CNS diseases, as well as in ischemia-reperfusion injury...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28644055/regulation-of-transient-receptor-potential-melastatin-4-channel-by-sarcoplasmic-reticulum-inositol-trisphosphate-receptors-role-in-human-detrusor-smooth-muscle-function
#20
Aaron Provence, Eric S Rovner, Georgi V Petkov
We recently reported key physiologic roles for Ca(2+)-activated transient receptor potential melastatin 4 (TRPM4) channels in detrusor smooth muscle (DSM). However, the Ca(2+)-signaling mechanisms governing TRPM4 channel activity in human DSM cells are unexplored. As the TRPM4 channels are activated by Ca(2+), inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca(2+) release from the sarcoplasmic reticulum represents a potential Ca(2+) source for TRPM4 channel activation. We used clinically-characterized human DSM tissues to investigate the molecular and functional interactions of the IP3Rs and TRPM4 channels...
September 3, 2017: Channels
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