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https://www.readbyqxmd.com/read/29774303/myotonia-permanens-with-nav1-4-g1306e-displays-varied-phenotypes-during-course-of-life
#1
Frank Lehmann-Horn, Adele D'Amico, Enrico Bertini, Mauro Lomonaco, Luciano Merlini, Kevin R Nelson, Heike Philippi, Gabriele Siciliano, Frank Spaans, Karin Jurkat-Rott
Introduction: Myotonia permanens due to Nav1.4-G1306E is a rare sodium channelopathy with potentially life-threatening respiratory complications. Our goal was to study phenotypic variability throughout life. Methods: Clinical neurophysiology and genetic analysis were performed. Using existing functional expression data we determined the sodium window by integration. Results: In 10 unrelated patients who were believed to have epilepsy, respiratory disease or Schwartz-Jampel syndrome, we made the same prima facie diagnosis and detected the same heterologous Nav1...
September 2017: Acta Myologica: Myopathies and Cardiomyopathies: Official Journal of the Mediterranean Society of Myology
https://www.readbyqxmd.com/read/29752399/common-coding-variants-in-scn10a-are-associated-with-the-nav1-8-late-current-and-cardiac-conduction
#2
Vincenzo Macri, Jennifer A Brody, Dan E Arking, William J Hucker, Xiaoyan Yin, Honghuang Lin, Robert W Mills, Moritz F Sinner, Steven A Lubitz, Ching-Ti Liu, Alanna C Morrison, Alvaro Alonso, Ning Li, Vadim V Fedorov, Paul M Janssen, Joshua C Bis, Susan R Heckbert, Elena V Dolmatova, Thomas Lumley, Colleen M Sitlani, L Adrienne Cupples, Sara L Pulit, Christopher Newton-Cheh, John Barnard, Jonathan D Smith, David R Van Wagoner, Mina K Chung, Gus J Vlahakes, Christopher J O'Donnell, Jerome I Rotter, Kenneth B Margulies, Michael P Morley, Thomas P Cappola, Emelia J Benjamin, Donna Muzny, Richard A Gibbs, Rebecca D Jackson, Jared W Magnani, Caroline N Herndon, Stephen S Rich, Bruce M Psaty, David J Milan, Eric Boerwinkle, Peter J Mohler, Nona Sotoodehnia, Patrick T Ellinor
BACKGROUND: Genetic variants at the SCN5A / SCN10A locus are strongly associated with electrocardiographic PR and QRS intervals. While SCN5A is the canonical cardiac sodium channel gene, the role of SCN10A in cardiac conduction is less well characterized. METHODS: We sequenced the SCN10A locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue...
May 2018: Circulation. Genomic and precision medicine
https://www.readbyqxmd.com/read/29737846/design-of-conformationally-constrained-acyl-sulfonamide-isosteres-identification-of-n-1-2-4-triazolo-4-3-a-pyridin-3-yl-methane-sulfonamides-as-potent-and-selective-hnav1-7-inhibitors-for-the-treatment-of-pain
#3
Thilo Focken, Sultan Chowdhury, Alla Zenova, Michael E Grimwood, Christine Chabot, Tao Sheng, Ivan Hemeon, Shannon M Decker, Michael Wilson, Paul Bichler, Qi Jia, Shaoyi Sun, Clint Young, Sophia Lin, Samuel J Goodchild, Noah G Shuart, Elaine Chang, Zhiwei Xie, Bowen Li, Kuldip Khakh, Girish Bankar, Matthew Waldbrook, Rainbow Kwan, Karen Nelkenbrecher, Parisa Karimi Tari, Navjot Chahal, Luis Sojo, C Lee Robinette, Andrew D White, Chien-An Chen, Yi Zhang, Jodie Pang, Jae H Chang, David H Hackos, James P Johnson, Charles J Cohen, Daniel Fred Ortwine, Daniel P Sutherlin, Christoph M Dehnhardt, Brian Salvatore Safina
The sodium channel NaV1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of NaV1.7, with high selectivity over the cardiac isoform NaV1.5. Herein, we report on the discovery of a novel series of N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)methanesulfonamides as selective NaV1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity...
May 8, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29736614/mir-183-5p-alleviates-chronic-constriction-injury-induced-neuropathic-pain-through-inhibition-of-trek-1
#4
Dan-Ni Shi, Yi-Tao Yuan, Dan Ye, Lu-Mei Kang, Jing Wen, Hong-Ping Chen
MicroRNAs have been implicated in nerve injury and neuropathic pain. In the previous study we had shown that miR-96 can attenuate neuropathic pain through inhibition of Nav1.3. In this study, we investigated the role of miR-183, a same cluster member of microRNA with miR-96, in neuropathic pain and its potential mechanisms. We found that the expression level of miR-183-5p in dorsal root ganglion was decreased with the development of neuropathic pain induced by chronic constriction sciatic nerve injury (CCI)...
May 7, 2018: Neurochemical Research
https://www.readbyqxmd.com/read/29719455/preemptive-application-of-qx-314-attenuates-trigeminal-neuropathic-mechanical-allodynia-in-rats
#5
Jeong-Ho Yoon, Jo-Young Son, Min-Ji Kim, Song-Hee Kang, Jin-Sook Ju, Yong-Chul Bae, Dong-Kuk Ahn
The aim of the present study was to examine the effects of preemptive analgesia on the development of trigeminal neuropathic pain. For this purpose, mechanical allodynia was evaluated in male Sprague-Dawley rats using chronic constriction injury of the infraorbital nerve (CCI-ION) and perineural application of 2% QX-314 to the infraorbital nerve. CCI-ION produced severe mechanical allodynia, which was maintained until postoperative day (POD) 30. An immediate single application of 2% QX-314 to the infraorbital nerve following CCI-ION significantly reduced neuropathic mechanical allodynia...
May 2018: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/29691127/digenic-heterozigosity-in-scn5a-and-cacna1c-explains-the-variable-expressivity-of-the-long-qt-phenotype-in-a-spanish-family
#6
Paloma Nieto-Marín, Juan Jiménez-Jáimez, David Tinaquero, Silvia Alfayate, Raquel G Utrilla, María Del Mar Rodríguez Vázquez Del Rey, Francesca Perin, Geòrgia Sarquella-Brugada, Lorenzo Monserrat, Josep Brugada, Luis Tercedor, Juan Tamargo, Eva Delpón, Ricardo Caballero
INTRODUCTION AND OBJECTIVES: A known long QT syndrome-related mutation in Nav1.5 cardiac channels (p.R1644H) was found in 4 members of a Spanish family but only 1 of them showed prolongation of the QT interval. In the other 3 relatives, a novel missense mutation in Cav1.2 cardiac channels was found (p.S1961N). Here, we functionally analyzed p.S1961N Cav1.2 channels to elucidate whether this mutation regulates the expressivity of the long QT syndrome phenotype in this family. METHODS: L-type calcium current (ICaL ) recordings were performed by using the whole-cell patch-clamp technique in Chinese hamster ovary cells transiently transfected with native and/or p...
April 21, 2018: Revista Española de Cardiología
https://www.readbyqxmd.com/read/29689688/swimming-exercise-induced-reversed-expression-of-mir-96-and-its-target-gene-nav1-3-in-diabetic-peripheral-neuropathy-in-rats
#7
Amir Mahmoudi Aghdam, Parviz Shahabi, Elham Karimi-Sales, Rafigheh Ghiasi, Saeed Sadigh-Eteghad, Javad Mahmoudi, Mohammad Reza Alipour
Diabetes is a common metabolic disease which leads to diabetic peripheral neuropathy. Recently, the role of microRNA-96 (miR-96) in alleviating neuropathic pain by inhibiting the expression of NaV1.3, an isoform of voltage-gated sodium channels, has been shown. Peripheral nerve injuries result in NaV1.3 elevation. Exercise has beneficial role in diabetes management and peripheral neuropathy. However, the effects of exercise on miR-96 and its target gene NaV1.3 in diabetic rats are unknown. Therefore, the present study investigated the effects of exercise training on the expression of miR-96 and NaV1...
April 25, 2018: Chinese Journal of Physiology
https://www.readbyqxmd.com/read/29534991/microtubular-remodeling-and-decreased-expression-of-nav1-5-with-enhanced-ehd4-in-cells-from-the-infarcted-heart
#8
Wen Dun, Peter Danilo, Peter J Mohler, Penelope A Boyden
Cardiac Na+ channel remodeling provides a critical substrate for generation of reentrant arrhythmias in border zones of the infarcted canine heart. Recent studies show that Nav1.5 cytoskeletal- and endosomal-based membrane trafficking and function are linked to tubulin, microtubular (MT) networks, and Eps15 homology domain containing proteins like EHD4. AIM: Our objective is to understand the relation of tubulin and EHD4 to Nav 1.5 channel protein remodeling observed in border zone cells (IZs) when arrhythmias are known to occur; that is, 3-h, 48-h and 5-day post coronary occlusion...
March 10, 2018: Life Sciences
https://www.readbyqxmd.com/read/29530619/o-glcnacylation-of-cardiac-nav1-5-contributes-to-the-development-of-arrhythmias-in-diabetic-hearts
#9
Peng Yu, Lili Hu, Jinyan Xie, Sisi Chen, Lin Huang, Zixuan Xu, Xiao Liu, Qiongqiong Zhou, Ping Yuan, Xia Yan, Jiejin Jin, Yang Shen, Wengen Zhu, Linghua Fu, Qi Chen, Jianhua Yu, Jianxin Hu, Qing Cao, Rong Wan, Kui Hong
BACKGROUND: Cardiovascular complications are major causes of mortality and morbidity in diabetic patients. The mechanisms underlying the progression of diabetic heart (DH) to ventricular arrhythmias are unclear. O-linked GlcNAcylation (O-GlcNAc) is a reversible post-translational modification for the regulation of diverse cellular processes. The purpose of this study was to assess whether the cardiac voltage-gated sodium channel (Nav1.5) is subjected to O-linked GlcNAcylation (O-GlcNAc), which plays an essential role in DH-induced arrhythmias...
February 27, 2018: International Journal of Cardiology
https://www.readbyqxmd.com/read/29509584/sodium-channel-nav1-3-is-expressed-by-polymorphonuclear-neutrophils-during-mouse-heart-and-kidney-ischemia-in-vivo-and-regulates-adhesion-transmigration-and-chemotaxis-of-human-and-mouse-neutrophils-in-vitro
#10
Marit Poffers, Nathalie Bühne, Christine Herzog, Anja Thorenz, Rongjun Chen, Faikah Güler, Axel Hage, Andreas Leffler, Frank Echtermeyer
BACKGROUND: Voltage-gated sodium channels generate action potentials in excitable cells, but they have also been attributed noncanonical roles in nonexcitable cells. We hypothesize that voltage-gated sodium channels play a functional role during extravasation of neutrophils. METHODS: Expression of voltage-gated sodium channels was analyzed by polymerase chain reaction. Distribution of Nav1.3 was determined by immunofluorescence and flow cytometry in mouse models of ischemic heart and kidney injury...
June 2018: Anesthesiology
https://www.readbyqxmd.com/read/29495239/-homocysteine-induces-calcium-overload-in-neonatal-rat-atrial-cells-through-activation-of-sodium-current-and-camk%C3%A2-%C3%AE
#11
L Han, Q B Dong, Y C Wei, A C Zheng, J X Li, K Hong, Y Q Wu, X S Cheng
Objective: To investigate the effect and related mechanism of homocysteine (Hcy) on calcium overload in neonatal rat atrial cells (NRICs). Methods: NRICs were assigned to 9 groups after culture for 3 days: (1) control group; (2) Hcy group (0, 50, 100, 200, 500 μmol/L for 48 hours); (3) antioxidant group (NAC, 10 μmol/L for 24 hours); (4) Hcy+NAC group (500 μmol/L Hcy for 48 hours, then treated with 10 μmol/L NAC for 24 hours); (5) calcium/calmodulin dependent protein kinase Ⅱδ (CaMKⅡδ) inhibitor group (KN-93, 3 μmol/L KN-93 for 5 hours); (6) specific sodium current inhibitor group (ELE, 1 μmol/L ELE for 5 hours); (7) Hcy+KN-93 group (500 μmol/L Hcy for 48 hours, then treated with 3 μmol/L KN-93 for 5 hours); (8) Hcy+ELE group (500 μmol/L Hcy for 48 hours, then treated with 1 μmol/L ELE for 5 hours; (9) Hcy+KN-93+ELE group (500 μmol/L Hcy for 48 hours, then treated with 3 μmol/L KN-93 and 1 μmol/L ELE for 5 hours)...
February 24, 2018: Zhonghua Xin Xue Guan Bing za Zhi
https://www.readbyqxmd.com/read/29474731/a-novel-mutation-of-dipeptidyl-aminopeptidase-like-protein-6-in-a-family-with-suspicious-idiopathic-ventricular-fibrillation
#12
Dong-Bo Ding, Liang-Liang Fan, Zhen Xiao, Hao Huang, Ya-Qin Chen, Shuai Guo, Zhong-Hua Liu, Rong Xiang
Background: Sudden cardiac death (SCD) occurs in a broad spectrum of cardiac pathologies and is an important cause of mortality in the general population. Idiopathic ventricular fibrillation (IVF) is a rare but important factor resulting in SCD. It is diagnosed in a resuscitated cardiac arrest victim underlying unknown cause, with documented ventricular fibrillation. Previous studies have demonstrated that mutations in dipeptidyl aminopeptidase-like protein-6 (DPP6) and cardiac sodium channel Nav1...
February 20, 2018: QJM: Monthly Journal of the Association of Physicians
https://www.readbyqxmd.com/read/29466837/mutations-in-scn3a-cause-early-infantile-epileptic-encephalopathy
#13
Tariq Zaman, Ingo Helbig, Ivana Babić Božović, Suzanne D DeBrosse, A Christina Bergqvist, Kimberly Wallis, Livija Medne, Aleš Maver, Borut Peterlin, Katherine L Helbig, Xiaohong Zhang, Ethan M Goldberg
OBJECTIVE: Voltage-gated sodium (Na+ ) channels underlie action potential generation and propagation and hence are central to the regulation of excitability in the nervous system. Mutations in the genes SCN1A, SCN2A, and SCN8A, encoding the Na+ channel pore-forming (α) subunits Nav1.1, 1.2, and 1.6, respectively, and SCN1B, encoding the accessory subunit β1 , are established causes of genetic epilepsies. SCN3A, encoding Nav1.3, is known to be highly expressed in brain, but has not previously been linked to early infantile epileptic encephalopathy...
April 2018: Annals of Neurology
https://www.readbyqxmd.com/read/29438128/toxins-in-pain
#14
Fernanda C Cardoso, Mahadhi Hasan, Tianjiao Zhao, Richard J Lewis
PURPOSE OF REVIEW: Pain is a distressing protective sensory experience warning of actual or potential tissue damage. Natural toxins have evolved to exploit pain and related neuronal pathways to facilitate prey capture and for defence, often producing either numbness, paralysis or intense pain by selectively modulating ion channels and receptors in pain pathways. Understanding how toxins modulate pain pathways can enhance our understanding of the physiological and pathological basis of pain...
June 2018: Current Opinion in Supportive and Palliative Care
https://www.readbyqxmd.com/read/29410612/na-v-1-9-potentiates-oxidized-phospholipid-induced-trp-responses-only-under-inflammatory-conditions
#15
Corinna Martin, Carolin Stoffer, Milad Mohammadi, Julian Hugo, Enrico Leipold, Beatrice Oehler, Heike L Rittner, Robert Blum
Oxidized phospholipids (OxPL) like oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) were recently identified as novel proalgesic targets in acute and chronic inflammatory pain. These endogenous chemical irritants are generated in inflamed tissue and mediate their pain-inducing function by activating the transient receptor potential channels TRPA1 and TRPV1 expressed in sensory neurons. Notably, prototypical therapeutics interfering with OxPL were shown to inhibit TRP channel activation and pain behavior...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29402340/whole-exome-sequencing-identifies-a-novel-scn5a-mutation-c335r-in-a-chinese-family-with-arrhythmia
#16
Hao Huang, Dong-Bo Ding, Liang-Liang Fan, Jie-Yuan Jin, Jing-Jing Li, Shuai Guo, Ya-Qin Chen, Rong Xiang
BACKGROUND: SCN5A encodes sodium-channel α-subunit Nav1.5. The mutations of SCN5A can lead to hereditary cardiac arrhythmias such as the long-QT syndrome type 3 and Brugada syndrome. Here we sought to identify novel mutations in a family with arrhythmia. METHODS: Genomic DNA was isolated from blood of the proband, who was diagnosed with atrial flutter. Illumina Hiseq 2000 whole-exome sequencing was performed and an arrhythmia-related gene-filtering strategy was used to analyse the pathogenic genes...
May 2018: Cardiology in the Young
https://www.readbyqxmd.com/read/29391559/substitutions-of-the-s4div-r2-residue-r1451-in-na-v-1-4-lead-to-complex-forms-of-paramyotonia-congenita-and-periodic-paralyses
#17
Hugo Poulin, Pascal Gosselin-Badaroudine, Savine Vicart, Karima Habbout, Damien Sternberg, Serena Giuliano, Bertrand Fontaine, Saïd Bendahhou, Sophie Nicole, Mohamed Chahine
Mutations in NaV 1.4, the skeletal muscle voltage-gated Na+ channel, underlie several skeletal muscle channelopathies. We report here the functional characterization of two substitutions targeting the R1451 residue and resulting in 3 distinct clinical phenotypes. The R1451L is a novel pathogenic substitution found in two unrelated individuals. The first individual was diagnosed with non-dystrophic myotonia, whereas the second suffered from an unusual phenotype combining hyperkalemic and hypokalemic episodes of periodic paralysis (PP)...
February 1, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29388177/tanshinone-iia-improves-painful-diabetic-neuropathy-by-suppressing-the-expression-and-activity-of-voltage-gated-sodium-channel-in-rat-dorsal-root-ganglia
#18
Ao Ri-Ge-le, Zhuang-Li Guo, Qi Wang, Bao-Jian Zhang, Da-Wei Kong, Wen-Qiang Yang, Yan-Bing Yu, Li Zhang
Painful diabetic neuropathy (PDN) is one of the intractable complications of diabetes mellitus, which manifest as exaggerated pain perception. Previous studies showed that Tanshinone IIA (TIIA), one of the major bioactive extracts of Salvia miltiorrhiza Bunge, have obvious analgesic effect on different types of pain process, and the underlying analgesic mechanisms are not fully understood. The present study combined the behavioral, electrophysiological and biochemical methods to elucidate the analgesic mechanism of TIIA, using streptozotocin (STZ)-induced PDN rat models...
January 31, 2018: Experimental and Clinical Endocrinology & Diabetes
https://www.readbyqxmd.com/read/29358197/impact-of-renal-denervation-on-atrial-arrhythmogenic-substrate-in-ischemic-model-of-heart-failure
#19
Shinya Yamada, Man-Cai Fong, Ya-Wen Hsiao, Shih-Lin Chang, Yung-Nan Tsai, Li-Wei Lo, Tze-Fan Chao, Yenn-Jiang Lin, Yu-Feng Hu, Fa-Po Chung, Jo-Nan Liao, Yao-Ting Chang, Hsing-Yuan Li, Satoshi Higa, Shih-Ann Chen
BACKGROUND: Myocardial infarction increases the risk of heart failure (HF) and atrial fibrillation. Renal denervation (RDN) might suppress the development of atrial remodeling. This study aimed to elucidate the molecular mechanism of RDN in the suppression of atrial fibrillation in a HF model after myocardial infarction. METHODS AND RESULTS: HF rabbits were created 4 weeks after coronary ligation. Rabbits were classified into 3 groups: normal control (n=10), HF (n=10), and HF-RDN (n=6)...
January 22, 2018: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29357519/enhanced-basal-late-sodium-current-appears-to-underlie-the-age-related-prolongation-of-action-potential-duration-in-guinea-pig-ventricular-myocytes
#20
Yejia Song, Luiz Belardinelli
Aging hearts have prolonged QT interval and are vulnerable to oxidative stress. Because the QT interval indirectly reflects the action potential duration (APD), we examined the hypotheses that 1) the APD of ventricular myocytes increases with age; 2) the age-related prolongation of APD is due to an enhancement of basal late Na+ current (INaL ); 3) inhibition of INaL may protect aging hearts from arrhythmogenic effects of hydrogen peroxide (H2 O2 ). Experiments were performed on ventricular myocytes isolated from one-month (young) and one-year (old) guinea pigs (GPs)...
December 14, 2017: Journal of Applied Physiology
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