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Late sodium current

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https://www.readbyqxmd.com/read/29222390/sodium-channel-remodeling-in-subcellular-microdomains-of-murine-failing-cardiomyocytes
#1
Mathilde R Rivaud, Esperanza Agullo-Pascual, Xianming Lin, Alejandra Leo-Macias, Mingliang Zhang, Eli Rothenberg, Connie R Bezzina, Mario Delmar, Carol Ann Remme
BACKGROUND: Cardiac sodium channel (NaV1.5) dysfunction contributes to arrhythmogenesis during pathophysiological conditions. Nav1.5 localizes to distinct subcellular microdomains within the cardiomyocyte, where it associates with region-specific proteins, yielding complexes whose function is location specific. We herein investigated sodium channel remodeling within distinct cardiomyocyte microdomains during heart failure. METHODS AND RESULTS: Mice were subjected to 6 weeks of transverse aortic constriction (TAC; n=32) to induce heart failure...
December 8, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29193076/resurgent-sodium-current-promotes-action-potential-firing-in-the-avian-auditory-brainstem
#2
Hui Hong, Ting Lu, Xiaoyu Wang, Yuan Wang, Jason Tait Sanchez
Auditory brainstem neurons are functionally primed to fire action potentials (APs) at markedly high-rates in order to rapidly encode acoustic information of sound. This specialization is critical for survival and the comprehension of behaviourally relevant communication functions, including sound localization and understanding speech in noise. Here, we investigated underlying ion channel mechanisms essential for high-rate AP firing in neurons of the chicken nucleus magnocellularis (NM) - the avian analog of bushy cells of the mammalian anteroventral cochlear nucleus...
November 28, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/29177922/sglt1-and-sglt1-inhibitors-a-role-to-be-assessed-in-the-current-clinical-practice
#3
Leonardo Spatola, Silvia Finazzi, Claudio Angelini, Marco Dauriz, Salvatore Badalamenti
Diabetes is a complex disease of increasingly common occurrence worldwide. Attaining optimal glycemic control is the main challenge to prevent the development of diabetes-related complications and/or to stop their progression. In recent years, the pharmacologic toolkit for the treatment of diabetes has considerably expanded, thus paving the way to more pathophysiology-oriented therapies. For instance, the sodium-glucose cotransporters SGLT2 and SGLT1 have been in the spotlight because of better knowledge of their physiology and therapeutic potential...
November 24, 2017: Diabetes Therapy: Research, Treatment and Education of Diabetes and related Disorders
https://www.readbyqxmd.com/read/29139614/human-dental-stem-cell-derived-transgene-free-ipscs-generate-functional-neurons-via-embryoid-body-mediated-and-direct-induction-methods
#4
Ikbale El Ayachi, Jun Zhang, Xiao-Ying Zou, Zongdong Yu, Wei Wei, Kristen M S O'Connell, George T-J Huang
Induced pluripotent stem cells (iPSCs) give rise to neural stem/progenitor cells (NSCs), serving as a good source for neural regeneration. Here, we established transgene-free (TF) iPSCs from dental stem cells (DSCs) and determined their capacity to differentiate into functional neurons in vitro. Generated TF iPSCs from stem cells of apical papilla (SCAP) and dental pulp stem cells (DPSCs) underwent two methods -- embryoid body (EB)-mediated and direct induction, to guide TF-DSC iPSCs along with H9 or H9 Syn-GFP (human embryonic stem cells) into functional neurons in vitro...
November 15, 2017: Journal of Tissue Engineering and Regenerative Medicine
https://www.readbyqxmd.com/read/29130489/angiotensin-1-7-modulates-electrophysiological-characteristics-and-calcium-homeostasis-in-pulmonary-veins-cardiomyocytes-via-mas-pi3k-enos-signaling-pathway
#5
Yen-Yu Lu, Wen-Shiann Wu, Yung-Kuo Lin, Chen-Chuan Cheng, Yao-Chang Chen, Shih-Ann Chen, Yi-Jen Chen
BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia, and pulmonary veins (PVs) play a critical role in triggering AF. Angiotensin (Ang)-(1-7) regulates calcium (Ca(2+) ) homeostasis and also plays a critical role in cardiovascular pathophysiology. However, the role of Ang-(1-7) in PV arrhythmogenesis remains unclear. MATERIALS AND METHODS: Conventional microelectrodes, whole-cell patch-clamp, and the Fluo-3 fluorimetric ratio technique were used to record ionic currents and intracellular Ca(2+) in isolated rabbit PV preparations, and in single isolated PV cardiomyocytes, before and after administration of Ang-(1-7)...
November 12, 2017: European Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29127493/late-sodium-current-associated-cardiac-electrophysiological-and-mechanical-dysfunction
#6
REVIEW
Shandong Yu, Gang Li, Christopher L-H Huang, Ming Lei, Lin Wu
Late sodium current (INaL) is a small sustained inward current observed during the cardiac action potential plateau phase following decay of the early peak INa. The endogenous INaL is relatively small in normal hearts but exerts functionally significant effects on cardiomyocyte repolarization with potentially pro-arrhythmic effects in hearts with reduced repolarization reserve. Enhanced INa,L occurs in long QT syndrome 3 (LQTS 3) patients, and under a number of pathological and pharmacological cardiovascular conditions, including bradycardia, myocardial ischemia, reperfusion injury, and heart failure...
November 10, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/29072259/barbaloin-inhibits-ventricular-arrhythmias-in-rabbits-by-modulating-voltage-gated-ion-channels
#7
Zhen-Zhen Cao, You-Jia Tian, Jie Hao, Pei-Hua Zhang, Zhi-Pei Liu, Wan-Zhen Jiang, Meng-Liu Zeng, Pei-Pei Zhang, Ji-Hua Ma
Barbaloin (10-β-D-glucopyranosyl-1,8-dihydroxy-3-(hydroxymethyl)-9(10H)-anthracenone) is extracted from the aloe plant and has been reported to have anti-inflammatory, antitumor, antibacterial, and other biological activities. Here, we investigated the effects of barbaloin on cardiac electrophysiology, which has not been reported thus far. Cardiac action potentials (APs) and ionic currents were recorded in isolated rabbit ventricular myocytes using whole-cell patch-clamp technique. Additionally, the antiarrhythmic effect of barbaloin was examined in Langendorff-perfused rabbit hearts...
October 26, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28972668/wenxin-keli-diminishes-ca-2-overload-induced-by-hypoxia-reoxygenation-in-cardiomyocytes-through-inhibiting-inal-and-ical
#8
Antao Luo, Zhipei Liu, Zhenzhen Cao, Jie Hao, Lin Wu, Chen Fu, Mengliu Zeng, Wanzhen Jiang, Peihua Zhang, Buchang Zhao, Tao Zhao, Jing Zhao, Jihua Ma
BACKGROUND: An increase in the late sodium current (INaL ) causes intracellular Na(+) overload and subsequently intracellular Ca(2+) ([Ca(2+) ]i ) overload via the stimulated reverse Na(+) -Ca(2+) exchange (NCX). Wenxin Keli (WXKL) is an effective antiarrhythmic Chinese herb extract, but the underlying mechanisms are unclear. METHODS AND RESULTS: The INaL , NCX current (INCX ), L-type Ca(2+) current (ICaL ) and action potentials (APs) were recorded using the whole-cell patch-clamp technique in rabbit ventricular myocytes...
October 3, 2017: Pacing and Clinical Electrophysiology: PACE
https://www.readbyqxmd.com/read/28971840/selective-inhibition-of-physiological-late-sodium-current-stabilizes-ventricular-repolarization
#9
Nesrine El-Bizri, Cindy Hong Li, Gong-Xin Liu, Sridharan Rajamani, Luiz Belardinelli
BACKGROUND: The physiological role of cardiac late Na+ current (INa) has not been well described. In this study, we tested the hypothesis that selective inhibition of physiological late INa abbreviates the normal action potential duration (APD) and counteracts the prolongation of APD and arrhythmic activities caused by inhibition of delayed rectifier K+ current, IKr. METHODS: The effects of GS-458967 (GS967) on the physiological late INa and action potentials (APs) in rabbit isolated ventricular myocytes and on the monophasic APs (MAPs) and arrhythmias in rabbit isolated perfused hearts were determined...
September 29, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28951728/urinary-exosomes-and-their-cargo-potential-biomarkers-for-mineralocorticoid-arterial-hypertension
#10
REVIEW
Eric R Barros, Cristian A Carvajal
Arterial hypertension (AHT) currently affects approximately 40% of adults worldwide, and its pathological mechanisms are mainly related to renal, vascular, and endocrine systems. Steroid hormones as aldosterone and cortisol are highly relevant to human endocrine physiology, and also to endocrine hypertension. Pathophysiological conditions, such as primary aldosteronism, affect approximately 10% of patients diagnosed with AHT and are secondary to a high production of aldosterone, increasing the risk also for cardiovascular damage and heart diseases...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28928044/electrocardiographic-biomarkers-to-confirm-drug-s-electrophysiological-effects-used-for-proarrhythmic-risk-prediction-under-cipa
#11
Jose Vicente, Meisam Hosseini, Lars Johannesen, David G Strauss
The ECG plays a critical role in the thorough QT study. This clinical study is part of the assessment of proarrhythmic potential of drugs under the current regulatory paradigm. While the current paradigm has been successful in preventing drugs with unexpected QT prolongation or torsade risk from reaching the market, the focus on QT prolongation has likely resulted in potentially beneficial compounds with minimal torsade risk being dropped from development. The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a new mechanistic-based paradigm for cardiac safety evaluation of drugs...
August 9, 2017: Journal of Electrocardiology
https://www.readbyqxmd.com/read/28924617/dynamics-of-sodium-current-mediated-early-afterdepolarizations
#12
Daisuke Sato, Colleen E Clancy, Donald M Bers
Early afterdepolarizations (EADs) have been attributed to two primary mechanisms: 1) recovery from inactivation of the L-type calcium (Ca) channel and/or 2) spontaneous Ca release, which depolarizes the membrane potential through the electrogenic sodium-calcium exchanger (NCX). The sodium (Na) current (INa), especially the late component of the Na current, has been recognized as an important player to set up the conditions for EADs by reducing repolarization reserve and increasing intracellular Na concentration, which leads to Ca overload...
September 2017: Heliyon
https://www.readbyqxmd.com/read/28913981/age-dependent-expression-of-nav1-9-channels-in-medial-prefrontal-cortex-pyramidal-neurons-in-rats
#13
Maciej Gawlak, Bartłomiej Szulczyk, Adam Berłowski, Katarzyna Grzelka, Anna Stachurska, Justyna Pełka, Katarzyna Czarzasta, Maciej Małecki, Przemysław Kurowski, Ewa Nurowska, Paweł Szulczyk
Developmental changes that occur in the prefrontal cortex during adolescence alter behavior. These behavioral alterations likely stem from changes in prefrontal cortex neuronal activity, which may depend on the properties and expression of ion channels. Nav1.9 sodium channels conduct a Na(+) current that is TTX resistant with a low threshold and noninactivating over time. The purpose of this study was to assess the presence of Nav1.9 channels in medial prefrontal cortex (mPFC) layer II and V pyramidal neurons in young (20-day old), late adolescent (60-day old), and adult (6- to 7-month old) rats...
December 2017: Developmental Neurobiology
https://www.readbyqxmd.com/read/28867216/the-effect-of-phosphorylation-on-the-salt-tolerance-related-functions-of-the-soybean-protein-pm18-a-member-of-the-group-3-lea-protein-family
#14
Yun Liu, Meiyan Yang, Hua Cheng, Nan Sun, Simu Liu, Shuiming Li, Yong Wang, Yizhi Zheng, Vladimir N Uversky
Enzymatically driven post-translated modifications (PTMs) usually happen within the intrinsically disordered regions of a target protein and can modulate variety of protein functions. Late embryogenesis abundant (LEA) proteins are a family of the plant intrinsically disordered proteins (IDPs). Despite their important roles in plant stress response, there is currently limited knowledge on the presence and functional and structural effects of phosphorylation on LEA proteins. In this study, we identified three phosphorylation sites (Ser(90), Tyr(136), and Thr(266)) in the soybean PM18 protein that belongs to the group-3 LEA proteins...
September 1, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28860774/bipolar-ii-disorder-as-the-initial-presentation-of-cadasil-an-underdiagnosed-manifestation
#15
Jianjun Wang, Jinfang Li, Fanxin Kong, Hanqing Lv, Zhouke Guo
Mood disturbances have been documented in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The highly varied morbidity indicates that the affective symptoms in CADASIL have not been cataloged systematically, leading to ineffective treatment, affecting the patients' quality of life, and possibly resulting in suicide. We present a case of CADASIL with bipolar II disorder as the first manifestation. A middle-aged female reported recurrent depressive episodes and appeared treatment resistant to adequate dosages and durations of antidepressants...
2017: Neuropsychiatric Disease and Treatment
https://www.readbyqxmd.com/read/28842436/ca-2-calmodulin-kinase-ii-dependent-regulation-of-atrial-myocyte-late-na-current-ca-2-cycling-and-excitability-a-mathematical-modeling-study
#16
Birce Onal, Daniel Gratz, Thomas J Hund
Atrial fibrillation (AF) affects more than 3 million people per year in the U.S., and is associated with high morbidity and mortality. Both electrical and structural remodeling contribute to AF, but the molecular pathways underlying AF pathogenesis are not well understood. Recently, a role for Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in regulation of persistent "late" sodium current (INa,L) has been identified. While INa,L inhibition is emerging as a potential antiarrhythmic strategy in AF patients, little is known about the mechanism linking INa,L to atrial arrhythmogenesis...
August 25, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28837385/mechanisms-and-models-of-cardiac-sodium-channel-inactivation
#17
Kathryn E Mangold, Brittany D Brumback, Paweorn Angsutararux, Taylor L Voelker, Wandi Zhu, Po Wei Kang, Jonathan D Moreno, Jonathan R Silva
Shortly after cardiac Na(+) channels activate and initiate the action potential, inactivation ensues within milliseconds, attenuating the peak Na(+) current, INa, and allowing the cell membrane to repolarize. A very limited number of Na(+) channels that do not inactivate carry a persistent INa, or late INa. While late INa is only a small fraction of peak magnitude, it significantly prolongs ventricular action potential duration, which predisposes patients to arrhythmia. Here, we review our current understanding of inactivation mechanisms, their regulation, and how they have been modeled computationally...
August 24, 2017: Channels
https://www.readbyqxmd.com/read/28756335/computational-approaches-to-understand-the-adverse-drug-effect-on-potassium-sodium-and-calcium-channels-for-predicting-tdp-cardiac-arrhythmias
#18
Mohsen Sharifi
Ion channels play a crucial role in the cardiovascular system. Our understanding of cardiac ion channel function has improved since their first discoveries. The flow of potassium, sodium and calcium ions across cardiomyocytes is vital for regular cardiac rhythm. Blockage of these channels, delays cardiac repolarization or tend to shorten repolarization and may induce arrhythmia. Detection of drug risk by channel blockade is considered essential for drug regulators. Advanced computational models can be used as an early screen for torsadogenic potential in drug candidates...
July 8, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28756098/phenotypic-variability-in-lqt3-human-induced-pluripotent-stem-cell-derived-cardiomyocytes-and-their-response-to-antiarrhythmic-pharmacologic-therapy-an-in-silico-approach
#19
Michelangelo Paci, Elisa Passini, Stefano Severi, Jari Hyttinen, Blanca Rodriguez
BACKGROUND: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are in vitro models with the clear advantages of their human origin and suitability for human disease investigations. However, limitations include their incomplete characterization and variability reported in different cell lines and laboratories. OBJECTIVE: The purpose of this study was to investigate in silico ionic mechanisms potentially explaining the phenotypic variability of hiPSC-CMs in long QT syndrome type 3 (LQT3) and their response to antiarrhythmic drugs...
November 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/28734073/differential-calcium-sensitivity-in-nav-1-5-mixed-syndrome-mutants
#20
Mena Abdelsayed, Alban-Elouen Baruteau, Karen Gibbs, Shubhayan Sanatani, Andrew D Krahn, Vincent Probst, Peter C Ruben
KEY POINTS: SCN5a mutations may express gain-of-function (Long QT Syndrome-3), loss-of-function (Brugada Syndrome 1) or both (mixed syndromes), depending on the mutation and environmental triggers. One such trigger may be an increase in cytosolic calcium, accompanying exercise. Many mixed syndromes mutants, including ∆KPQ, E1784K, 1795insD and Q1909R, are found in calcium-sensitive regions. Elevated cytosolic calcium attenuates gain-of-function properties in ∆KPQ, 1795insD and Q1909R, but not in E1784K...
September 15, 2017: Journal of Physiology
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