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T-type calcium channel

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https://www.readbyqxmd.com/read/29343689/a-novel-%C3%AE-conopeptide-eu1-6-inhibits-n-type-cav2-2-calcium-channels-and-exhibits-potent-analgesic-activity
#1
Zhuguo Liu, Peter Bartels, Mahsa Sadeghi, Tianpeng Du, Qing Dai, Cui Zhu, Shuo Yu, Shuo Wang, Mingxin Dong, Ting Sun, Jiabin Guo, Shuangqing Peng, Ling Jiang, David J Adams, Qiuyun Dai
We here describe a novel α-conopeptide, Eu1.6 from Conus eburneus, which exhibits strong anti-nociceptive activity by an unexpected mechanism of action. Unlike other α-conopeptides that largely target nicotinic acetylcholine receptors (nAChRs), Eu1.6 displayed only weak inhibitory activity at the α3β4 and α7 nAChR subtypes and TTX-resistant sodium channels, and no activity at TTX-sensitive sodium channels in rat dorsal root ganglion (DRG) neurons, or opiate receptors, VR1, KCNQ1, L- and T-type calcium channels expressed in HEK293 cells...
January 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29338087/thrombospondin-4-acts-on-pre-synaptic-calcium-channel-alpha-2-delta-1-subunit-to-induce-synaptogenesis-between-sensory-and-spinal-cord-neurons-through-a-t-type-calcium-channel-dependent-pathway-that-is-blocked-by-early-low-dose-gabapentin-treatments
#2
Yanhui Peter Yu, Nian Gong, Tae Dong Kweon, Benjamin Vo, Z David Luo
BACKGROUND AND PURPOSE: Nerve injury induces concurrent upregulation of calcium channel alpha-2-delta-1 subunit (Cav α2 δ1 ) and extracellular matrix protein thrombospondin-4 (TSP4) in dorsal root ganglia and dorsal spinal cord, leading to neuropathic pain state development. Interactions of these proteins promote aberrant excitatory synaptogenesis that contributes to neuropathic pain state development through unknown mechanisms. We investigated the contributory role of Cav α2 δ1 /TSP4 to synaptogenesis, and pathway involved in vitro, and whether gabapentin could block this process and pain development in vivo...
January 16, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29333726/calcium-current-properties-in-dystrophin-deficient-ventricular-cardiomyocytes-from-aged-mdx-mice
#3
Lena Rubi, Hannes Todt, Helmut Kubista, Xaver Koenig, Karlheinz Hilber
Duchenne muscular dystrophy (DMD), caused by mutations in the gene encoding for the cytoskeletal protein dystrophin, is linked with severe cardiac complications including cardiomyopathy development and cardiac arrhythmias. We and others recently reported that currents through L-type calcium (Ca) channels were significantly increased, and channel inactivation was reduced in dystrophin-deficient ventricular cardiomyocytes derived from the mdx mouse, the most commonly used animal model for human DMD. These gain-of-function Ca channel abnormalities may enhance the risk of Ca-dependent arrhythmias and cellular Ca overload in the dystrophic heart...
January 2018: Physiological Reports
https://www.readbyqxmd.com/read/29279414/t-tubule-remodeling-and-increased-heterogeneity-of-calcium-release-during-the-progression-to-heart-failure-in-intact-rat-ventricle
#4
Jasleen K Singh, Varderes Barsegyan, Nikhil Bassi, William Marszalec, Shannon Tai, Shruthi Mothkur, Maaz Mulla, Elsa Nico, Yohannes Shiferaw, Gary L Aistrup, John Andrew Wasserstrom
A highly organized transverse-tubule (TT) system is essential to normal Ca2+ cycling and cardiac function. We explored the relationship between the progressive disruption of TTs and resulting Ca2+ cycling during the development of heart failure (HF). Confocal imaging was used to measure Ca2+ transients and 2-D z-stack images in left ventricular epicardial myocytes of intact hearts from spontaneously hypertensive rats (SHR) and Wistar-Kyoto control rats. TT organization was measured as the organizational index (OI) derived from a fast Fourier transform of TT organization...
December 2017: Physiological Reports
https://www.readbyqxmd.com/read/29274077/increasing-t-type-calcium-channel-activity-by-%C3%AE-adrenergic-stimulation-contributes-to-%C3%AE-adrenergic-regulation-of-heart-rates
#5
Yingxin Li, Xiaoxiao Zhang, Chen Zhang, Xiaoying Zhang, Ying Li, Zhao Qi, Christopher Szeto, Mingxin Tang, Yizhi Peng, Jeffery D Molkentin, Steven R Houser, Mingxing Xie, Xiongwen Chen
OBJECTIVE: Cav3.1 (α1G ) T-type Ca2+ channel (TTCC) is expressed in mouse sinoatrial node cells (SANCs) and atrioventricular nodal (AVN) cells and contributes to heart rate genesis and AV conduction. However, its role in heart rate (HR) regulation and AV conduction acceleration by the β-adrenergic system (SAS) is unclear, which is the topic of this study. METHODS AND RESULTS: L- (ICa-L ) and T-type (ICa-T ) Ca2+ currents were recorded in SANCs from Cav3.1 transgenic (TG) and knockout (KO), and control mice...
December 23, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/29216332/voltage-dependent-calcium-channel-signaling-mediates-gabaa-receptor-induced-migratory-activation-of-dendritic-cells-infected-by-toxoplasma-gondii
#6
Sachie Kanatani, Jonas M Fuks, Einar B Olafsson, Linda Westermark, Benedict Chambers, Manuel Varas-Godoy, Per Uhlén, Antonio Barragan
The obligate intracellular parasite Toxoplasma gondii exploits cells of the immune system to disseminate. Upon T. gondii-infection, γ-aminobutyric acid (GABA)/GABAA receptor signaling triggers a hypermigratory phenotype in dendritic cells (DCs) by unknown signal transduction pathways. Here, we demonstrate that calcium (Ca2+) signaling in DCs is indispensable for T. gondii-induced DC hypermotility and transmigration in vitro. We report that activation of GABAA receptors by GABA induces transient Ca2+ entry in DCs...
December 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29213100/altered-spontaneous-calcium-signaling-of-in-situ-chondrocytes-in-human-osteoarthritic-cartilage
#7
Xiaoyuan Gong, Wenbin Xie, Bin Wang, Lingchuan Gu, Fuyou Wang, Xiang Ren, Cheng Chen, Liu Yang
Intracellular calcium ([Ca2+]i) signaling is an essential universal secondary messenger in articular chondrocytes. However, little is known about its spatiotemporal features in the context of osteoarthritis (OA). Herein, by examining the cartilage samples collected from patients undergoing knee arthroscopic surgery, we investigated the spatiotemporal features of spontaneous [Ca2+]i signaling in in situ chondrocytes at different OA stages. Our data showed zonal dependent spontaneous [Ca2+]i signaling in healthy cartilage samples under 4 mM calcium environment...
December 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29212024/cell-type-specific-splicing-of-piezo2-regulates-mechanotransduction
#8
Marcin Szczot, Leah A Pogorzala, Hans Jürgen Solinski, Lynn Young, Philina Yee, Claire E Le Pichon, Alexander T Chesler, Mark A Hoon
Piezo2 is a mechanically activated ion channel required for touch discrimination, vibration detection, and proprioception. Here, we discovered that Piezo2 is extensively spliced, producing different Piezo2 isoforms with distinct properties. Sensory neurons from both mice and humans express a large repertoire of Piezo2 variants, whereas non-neuronal tissues express predominantly a single isoform. Notably, even within sensory ganglia, we demonstrate the splicing of Piezo2 to be cell type specific. Biophysical characterization revealed substantial differences in ion permeability, sensitivity to calcium modulation, and inactivation kinetics among Piezo2 splice variants...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29207174/calcium-channels-are-involved-in-ephb-ephrinb-reverse-signaling%C3%A2-induced-apoptosis-in-a-rat-chronic-ocular-hypertension-model
#9
Lingdan Dong, Xianglin Cheng, Long Zhou, Yanhong Hu
Erythropoietin-producing hepatocyte receptor B (EphB)/ephrinB reverse signaling has been revealed to be activated in chronic ocular hypertension (COH) by increasing the apoptosis of retinal ganglion cells (RGCs). However, the exact mechanism is not well understood. The present study investigated the involvement of Ca2+ channels in the apoptosis of RGCs induced by EphB/ephrinB reverse signaling in a rat CHO model, which was established by cauterizing 3 out of the 4 episcleral veins. The expression levels of four voltage‑gated Ca2+ channel subunits (Cav3...
November 27, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29206482/brain-circuits-and-neurochemical-systems-in-essential-tremor-insights-into-current-and-future-pharmacotherapeutic-approaches
#10
Sara M Schaefer, Ana Vives Rodriguez, Elan D Louis
There are few medications that are available for the treatment of essential tremor (ET) and they are only moderately effective. Areas covered: Data were obtained from a PubMed search. Original articles, review articles, and clinical guidelines were included. Two disease models for ET have been proposed: 1) the olivary model, which attributes ET to a pathological pacemaker in the inferior olivary nucleus, and 2) the cerebellar degeneration model, which postulates that ET originates in the cerebellum and could be related to deficient or abnormal Purkinje cell (PC) output...
December 5, 2017: Expert Review of Neurotherapeutics
https://www.readbyqxmd.com/read/29186694/large-scale-cognitive-gwas-meta-analysis-reveals-tissue-specific-neural-expression-and-potential-nootropic-drug-targets
#11
Max Lam, Joey W Trampush, Jin Yu, Emma Knowles, Gail Davies, David C Liewald, John M Starr, Srdjan Djurovic, Ingrid Melle, Kjetil Sundet, Andrea Christoforou, Ivar Reinvang, Pamela DeRosse, Astri J Lundervold, Vidar M Steen, Thomas Espeseth, Katri Räikkönen, Elisabeth Widen, Aarno Palotie, Johan G Eriksson, Ina Giegling, Bettina Konte, Panos Roussos, Stella Giakoumaki, Katherine E Burdick, Antony Payton, William Ollier, Ornit Chiba-Falek, Deborah K Attix, Anna C Need, Elizabeth T Cirulli, Aristotle N Voineskos, Nikos C Stefanis, Dimitrios Avramopoulos, Alex Hatzimanolis, Dan E Arking, Nikolaos Smyrnis, Robert M Bilder, Nelson A Freimer, Tyrone D Cannon, Edythe London, Russell A Poldrack, Fred W Sabb, Eliza Congdon, Emily Drabant Conley, Matthew A Scult, Dwight Dickinson, Richard E Straub, Gary Donohoe, Derek Morris, Aiden Corvin, Michael Gill, Ahmad R Hariri, Daniel R Weinberger, Neil Pendleton, Panos Bitsios, Dan Rujescu, Jari Lahti, Stephanie Le Hellard, Matthew C Keller, Ole A Andreassen, Ian J Deary, David C Glahn, Anil K Malhotra, Todd Lencz
Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor...
November 28, 2017: Cell Reports
https://www.readbyqxmd.com/read/29180451/molecular-mimicking-of-c-terminal-phosphorylation-tunes-the-surface-dynamics-of-cav1-2-calcium-channels-in-hippocampal-neurons
#12
Alessandra Folci, Angela Steinberger, Boram Lee, Ruslan Stanika, Susanne Scheruebel, Marta Campiglio, Claudia Ramprecht, Brigitte Pelzmann, Johannes W Hell, Gerald J Obermair, Martin Heine, Valentina Di Biase
L-type voltage gated CaV1.2 calcium channels (CaV1.2) are key regulators of neuronal excitability, synaptic plasticity, and excitation-transcription coupling. Surface exposed CaV1.2 distributes in clusters along the dendrites of hippocampal neurons. A permanent exchange between stably clustered and laterally diffusive extra-clustered channels maintains steady-state levels of CaV1.2 at dendritic signaling domains. A dynamic equilibrium between anchored and diffusive receptors is a common feature among ion channels and is crucial to modulate signaling transduction...
November 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29179637/cone-dystrophy-and-ectopic-synaptogenesis-in-a-cacna1f-loss-of-function-model-of-congenital-stationary-night-blindness-csnb2a
#13
D M Waldner, N C Giraldo Sierra, S Bonfield, L Nguyen, I S Dimopoulos, Y Sauvé, W K Stell, N T Bech-Hansen
Congenital stationary night blindness 2A (CSNB2A) is an X-linked retinal disorder, characterized by phenotypically variable signs and symptoms of impaired vision. CSNB2A is due to mutations in CACNA1F, which codes for the pore-forming α1F subunit of a L-type voltage-gated calcium channel, Cav1.4. Mouse models of CSNB2A, used for characterizing the effects of various Cacna1f mutations, have revealed greater severity of defects than in human CSNB2A. Specifically, Cacna1f-knockout mice show an apparent lack of visual function, gradual retinal degeneration, and disruption of photoreceptor synaptic terminals...
November 28, 2017: Channels
https://www.readbyqxmd.com/read/29165691/estradiol-protects-proopiomelanocortin-neurons-against-insulin-resistance
#14
Jian Qiu, Martha A Bosch, Cecilia Meza, Uyen-Vy Navarro, Casey C Nestor, Edward J Wagner, Oline K Rønnekleiv, Martin J Kelly
Insulin resistance is at the core of the metabolic syndrome, and men exhibit a higher incidence of metabolic syndrome than women in early adult life, but this sex advantage diminishes sharply when women reach the postmenopausal state. Since 17β-estradiol (E2) augments the excitability of the anorexigenic POMC neurons, we investigated the neuroprotective effects of E2 against insulin resistance in POMC neurons from diet-induced obese (DIO) female and male mice. The efficacy of insulin to activate canonical transient receptor potential 5 (TRPC5) channels and depolarize POMC neurons was significantly reduced in DIO male but not in DIO female mice...
November 20, 2017: Endocrinology
https://www.readbyqxmd.com/read/29163766/epigallocatechin-3-gallate-egcg-up-regulates-mir-15b-expression-thus-attenuating-store-operated-calcium-entry-soce-into-murine-cd4-t-cells-and-human-leukaemic-t-cell-lymphoblasts
#15
Shaqiu Zhang, Tamer Al-Maghout, Rosi Bissinger, Ni Zeng, Lisann Pelzl, Madhuri S Salker, Anchun Cheng, Yogesh Singh, Florian Lang
CD4(+) T cells are key elements in immune responses and inflammation. Activation of T cell receptors in CD4(+) T cells triggers cytosolic Ca(2+) release with subsequent store operated Ca(2+) entry (SOCE), which is accomplished by the pore forming Ca(2+) release activated Ca(2+) (CRAC) channel Orai1 and its regulator stromal cell-interaction molecule 2 (STIM2). Green tea polyphenol epigallocatechin-3-gallate (EGCG) acts as a potent anti-inflammatory and anti-oxidant agent for various types of cells including immune cells...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29126879/mechanical-stretch-increases-l-type-calcium-channel-stability-in-cardiomyocytes-through-a-polycystin-1-akt-dependent-mechanism
#16
A Córdova-Casanova, I Olmedo, J A Riquelme, G Barrientos, G Sánchez, T G Gillette, S Lavandero, M Chiong, P Donoso, Z Pedrozo
The L-type calcium channel (LTCC) is an important determinant of cardiac contractility. Therefore, changes in LTCC activity or protein levels could be expected to affect cardiac function. Several studies describing LTCC regulation are available, but only a few examine LTCC protein stability. Polycystin-1 (PC1) is a mechanosensor that regulates heart contractility and is involved in mechanical stretch-induced cardiac hypertrophy. PC1 was originally described as an unconventional Gi/o protein-coupled receptor in renal cells...
November 7, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29116786/discovery-of-a-potent-selective-t-type-calcium-channel-blocker-as-a-drug-candidate-for-the-treatment-of-generalized-epilepsies
#17
Olivier Bezençon, Bibia Heidmann, Romain Siegrist, Simon Stamm, Sylvia Richard, Davide Pozzi, Olivier Corminboeuf, Catherine Roch, Melanie Kessler, Eric A Ertel, Isabelle Reymond, Thomas Pfeifer, Ruben de Kanter, Michael Toeroek-Schafroth, Luca G Moccia, Jacques Mawet, Richard Moon, Markus Rey, Bruno Capeleto, Elvire Fournier
We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as clinical candidate.
November 8, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29100477/activation-of-anoctamin-1-limits-pulmonary-endothelial-cell-proliferation-via-p38-mapk-dependent-apoptosis
#18
Ayed M Allawzi, Alexander Vang, Richard T Clements, Bong Sook Jhun, Nouaying R Kue, Thomas J Mancini, Amy K Landi, Dmitry Terentyev, Jin O-Uchi, Suzy A Comhair, Serpil C Erzurum, Gaurav Choudhary
Hyperproliferative endothelial cells (ECs) play an important role in the pathogenesis of PAH. Anoctamin-1 (Ano1), a calcium activated chloride channel, can regulate cell proliferation and cell cycle in multiple cell types. However, the expression and function of Ano1 in the pulmonary endothelium is unknown. We examined whether Ano1 was expressed in pulmonary ECs and if altering Ano1 activity would affect EC survival. Expression and localization of Ano1 in rat lung microvascular ECs (RLMVECs) was assessed using immunoblot, immunofluorescence, and subcellular fractionation...
November 3, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/29082441/deletion-of-t-type-calcium-channels-cav3-1-or-cav3-2-attenuates-endothelial-dysfunction-in-aging-mice
#19
Anne D Thuesen, Kenneth Andersen, Kristina S Lyngsø, Mark Burton, Charlotte Brasch-Andersen, Paul M Vanhoutte, Pernille B L Hansen
Impairment of endothelial function with aging is accompanied by reduced nitric oxide (NO) production. T-type Cav3.1 channels augment nitric oxide and co-localize with eNOS. Therefore, the hypothesis was that T-type channels contribute to the endothelial dysfunction of aging. Endothelial function was determined in mesenteric arteries (perfusion) and aortae (isometric contraction) of young and old wild-type (WT), Cav3.1, and Cav3.2 knockout mice. NO production was measured by fluorescence imaging in mesenteric arteries...
October 29, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/29074257/discovery-and-evaluation-of-cav3-2-selective-t-type-calcium-channel-blockers
#20
Olivier Bezençon, Luboš Remeň, Sylvia Richard, Catherine Roch, Melanie Kessler, Eric A Ertel, Richard Moon, Jacques Mawet, Thomas Pfeifer, Bruno Capeleto
We identified and characterized a series of pyrrole amides as potent, selective Cav3.2-blockers. This series culminated with the identification of pyrrole amides 13b and 26d, with excellent potencies and/or selectivities toward the Cav3.1- and Cav3.3-channels. These compounds display poor physicochemical and DMPK properties, making their use difficult for in vivo applications. Nevertheless, they are well-suited for in vitro studies.
September 30, 2017: Bioorganic & Medicinal Chemistry Letters
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