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SCN5A activates sodium(1+). 52 / 52
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"Mutations in SCN5A may cause sodium channel dysfunction by decreasing peak sodium current, which slows conduction and facilitates reentry based arrhythmias, and by enhancing late sodium current, which prolongs the action potential and sets the stage for early afterdepolarization and arrhythmias."
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"Authors ' replyWe are pleased with Ibrahim El-Battrawy and colleagues ' interest in our work.1 We note that the authors are concerned that the sodium current recordings in our patch clamp experiments could have been contributed to by NaV1.5."
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"The former contributes to the development of cardiac fibrosis by affecting the initiation and propagation of electrical stimuli, for instance, the reduced I significantly increased collagen deposition in SCN5A-knockout mice.2 SCN5A gene produces α-subunit of the cardiac sodium voltage-gated channel (Nav1.5) arbitrates the rapid Na influx, which is crucial for the upstroke of action potential and excitation of cardiac cells.3 4 Structural changes in Nav1.5 channel syndicate a spectrum of arrhythmic disorders that lead to sudden cardiac death."
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"Nav1.5/Kir2.x reciprocal modulation has been elucidated previously through a critical domain of Nav1.5, which increases the sodium and potassium currents (Matamoros et al., 2016)."
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"The cardiac Nav1.5 mediated sodium current (I Na ) generates the upstroke of the action potential in atrial and ventricular myocytes."
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"Hundreds of SCN5A variants have been reported leading to abnormal function of sodium ion channels and myocardial repolarization disorder [18, 19], including BrS, LQTS, SSS, etc. Abnormal sodium ion channels caused by SCN5A gene variant can be activated by high temperature, so BrS has a higher probability of incidence in high temperature regions which may help to explain the summer aggregation of SUD in some epidemic areas [20]."
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"Gain-of-function mutations in SCN5A , the gene encoding the alpha subunit of the cardiac sodium channel, cause increased late sodium current (I Na,L ) which prolongs the action potential (AP)."
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"Since a synonymous nucleotide change in the SCN5A gene is unlikely to induce the functional change of the sodium channel, a non synonymous substitution was considered as a candidate for the mutation a[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Activation of human macrophage SCN5A by cytoplasmic poly I:C, a mimic of viral dsRNA, increases the inward sodium current and leads to increased transcription of anti-viral genes through an ATF2-depen[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"RANGRF (RAN Guanine Nucleotide Release Factor), commonly known as MOG1, modulates the development and functioning of the NaV1.5 cardiac sodium channel in individuals by augmenting the expression of NaV1.5 at the cell membrane, thereby raising sodium current density [119]."
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"In approximately 20% of the cases BrS is caused by mutations in the SCN5A gene on chromosome 3p21-23, encoding the cardiac sodium channel, a protein involved in the control of myocardial excitability."
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"The recombinant toxin could serve as a tool for studying ion channel modulation in cancer cells, potentially offering insights into new therapeutic strategies.Our finding that nChcoh-43 and rChcoh-43 alone had no significant impact on MCF-7 cell viability aligns with previous research by Driffort et al. [23], who reported that Nav1.5 inhibition using ranolazine at 50 µM reduced sodium currents in MDA-MB-231 cells without affecting cell viability."
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"Concurrently elevating extracellular sodium and increasing intercalated disc edema prolongs repolarization more than the individual interventions alone in the LQT3."
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"LQT3 includes gain-of-function mutation (SCN5A gene) in the sodium channel (phase 0 of an action potential) that causes persistent sodium influx that extends through the plateau phase."
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"In contrast we did find a significant increase in expression (~ 2 fold) in Galpha i2 (-/-) mice of the calcium channel alpha subunit, CACNA1C (Ca v 1.2), which underlies the L-type calcium current and SCN5A which underlies the rapidly inactivating sodium current in ventricular myocytes (XREF_TABLE)."
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"However, the mechanism of malignant ventricular arrhythmia in LVNC patients remains unclear, and there is no special treatment method for LVNC.The SCN5A gene encodes a major cardiac voltage-gated sodium channel called NaV1.5, which mediates the sodium ion permeability of cardiac cells and maintains the normal function of the inward sodium current (I )."
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"It has previously been shown that a common polymorphism of SCN5A, H558R, significantly potentiates the sodium current in the presence of the Fetal spliceoform, however only a few studies have examined the developmental expression of the Fetal and Adult SCN5A spliceoforms ."
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"Interestingly, the latter two genes were also involved in the entrainment of the circadian clock.The biological process of atrial cardiac muscle cell action potential includes the genes Cacnb2, Scn5a and Kcna5, which modulate calcium, sodium, and potassium transport in excitable membranes, respectively, as well as the involvement of Ank2 in signal transduction."
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"These results demonstrate that a variant of NaV1.6 participates in the control of podosome and invadopodia formation and suggest that intracellular sodium release mediated by NaV1.6 may regulate cellular invasion of macrophages and melanoma cells."
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"Mutations in KCNQ1 (LQT1) and HERG (LQT2) cause defects in the delayed rectifier potassium currents, [XREF_BIBR XREF_BIBR] whereas mutations in SCN5A (LQT3) cause a persistent cardiac sodium current."
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"Nav1.5 channels mediate inward sodium currents (INa) and induce fast depolarization to initiate an intracellular excitation-contraction coupling cascade."
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"Mutations in SCN5A have also been shown to cause the sodium channel to turn off prematurely and thus to set the stage for the development of a rapid polymorphic ventricular tachycardia and ventricular fibrillation in patients with the Brugada Syndrome."
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"A390V-SNTA1 expressed with SCN5A, nNOS, and PMCA4b in heterologous cells increased peak and late sodium current compared with WT-SNTA1, and the increase was partially inhibited by NOS blockers."
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"EGF was shown to increase metastatic potential of prostate cancer by up regulation of SCN9A; and hence, the authors have presumed that the mutations in SCN5A and SCN9A may increase the activity of sodium channels thereby increasing the invasive potential of glioblastoma [37]."
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"175 SQTL3 accounts for approximately 10% of all mutations diagnosed in LQTS, due to changes in the SCN5A gene, whose functional gain produces a continuous sodium input during the plateau phase, which facilitates early depolarization in cardiac cells."
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"As compared to the expression of SCN5A alone, coexpression of both SCN5A and VCL can increase sodium current density by = ~ 30% but did not change the sodium channel 's activation and inactivation properties."
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"NaV1.6 underlies the nodal sodium current in myelinated axons [XREF_BIBR] while unmyelinated axons may express NaV1.7 and possibly NaV1.6 [XREF_BIBR] together with the TTX-r isoforms NaV1.8 and NaV1.9 [XREF_BIBR]."
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"Since a non synonymous nucleotide change in the SCN5A gene is likely to induce a functional change in the sodium channel, a non synonymous substitution was considered a candidate for the variation associated with this disorder."
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"We demonstrated that a paroxysmal extreme pain disorder (PEPD) mutation in the human peripheral neuronal sodium channel Nav1.7, a paramyotonia congenita (PMC) mutation in the human skeletal muscle sodium channel Nav1.4, and a long-QT3/SIDS mutation in the human cardiac sodium channel Nav1.5 all substantially increased the amplitude of resurgent sodium currents in an optimized adult rat-derived dorsal root ganglion neuronal expression system."
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"[1,2] During the last 20 years, the genetic basis of Brugada syndrome has been extensively investigated, leading to major changes in gene encoding of the alpha-subunit of the Nav1.5 (SCN5A, driving the fast depolarising sodium current), the gene most frequently associated with functional abnormalities underlying arrhythmogenicity."
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"Inhibition of NaV1.5 by TTX prevented phagocytosis, sodium efflux and endosomal acidification [28] ."
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"In addition, sodium channel dysfunction caused by mutations in the SCN5A gene, encoding the major sodium channel in heart, is associated with a number of relatively uncommon arrhythmia syndromes, incl[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"The phosphorylation level of Nav1.5 and α1 subunit of L-type calcium channel (Cav1.2) can both be increased by CaMKII activation, which further enhances late sodium current (I Na,L ) and L-type calciu[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Possible explanations for our case are : (1) the proband but not his father carries unidentified BrS susceptibility gene (s), and/or (2) the father but not the proband carries unknown genetic variant (s) that can rescue or mitigate the BrS phenotype and restore the sodium channel dysfunctions caused by SCN5A gene defects."
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"Because of these mutations, the voltage-dependent sodium current is potentiated in this subtype by incomplete Nav1.5 inactivation [28]."
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"SCN5A loss-of-function mutations further reduce sodium influx and shorten action potential duration, increasing the risk of AF."
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"Confirms that NaV1.9 underlies the persistent sodium current.137."
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"For example, patients with LQT3, caused by mutations in the cardiac sodium channel gene SCN5A that inappropriately activate and open the sodium channel, respond to sodium channel blockers such as flecainide) 9 LQT3 patients are more likely to have arrhythmias at times of bradycardia."
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"The sodium voltage-gated channel alpha subunit 5 gene (SCN5A) gene encodes the pore forming α-subunit, Nav1.5 protein, which mediates the inward sodium current (I ) [3,4,5] in cardiac muscle."
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"Similar to BrS, loss-of-function SCN5A variants could decrease sodium channel availability and led to PCCD, while gain-of-function SCN5A variants underlying LQT3 could prolong AP and increased persistent inward sodium, which might also occur in PCCD."
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"Class I antiarrhythmic agents such as flecainide, lidocaine and mexiletine generally block I (NA (P)) more potently than block of I (Na (T)) and have been used clinically to treat LQT3 syndrome, which arises because mutations in SCN5A produce defective inactivation of the cardiac sodium channel."
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"SCN5A variants causing increased sodium current during the plateau phase of the cardiac action potential is associated with Long QT Syndrome type 3 (LQTS3), Torsade de Pointes ventricular tachycardia and SCD."
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"Malfunction of the SCN5A ion current inactivation has particularly been observed in a congenital form and has also been correlated to a prolonged QT interval (denoted LQT3) and clinical observations o[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"For example, IL-1beta exposure can lead to the activation of extracellular signal regulated kinase (ERK) (Lu et al. 2005; Dobierzewska et al. 2012), which has been reported to directly phosphorylate specific residues within intracellular loop 1 (L1) of the NaV1.7 sodium channel, thereby allowing sodium channel activation at more hyperpolarized potentials (Stamboulian et al. 2010)."
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"Brugada syndrome is an inherited cardiac disorder caused by mutations in the SCN5A gene encoding the cardiac sodium channel alpha subunit, which can lead ventricular fibrillation and sudden death."
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"Recent studies have shown that prolonged exposure to some drugs with known diLQTS risk can also prolong repolarization by enhancing late sodium current (I ) in dog and mouse cardiomyocytes, as in the SCN5A-linked form of cLQTS (LQT3)."
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"In vitro studies showed that the polymorphism in the SCN5A gene increases the rate of cardiac sodium channel activation.In summary, no specific genetic polymorphism or haplotypes explaining a large fraction of diLQTS risk are known until now.In this last part of the review, the authors discuss the evidence for QT prolongation with methadone treatment, risk factors, monitoring and therapeutic alternatives.6."
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"The genetic type 3 of this syndrome (LQT3) is caused by gain-of-function mutations in the SCN5A cardiac sodium channel gene which mediates the fast Na v 1.5 current during action potential initiation."
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"Gain-of-function mutations in SCN5A can cause additional sodium influx into cardiomyocytes through aberrant channel gating, leading to long QT syndrome ( Wilde & Amin, 2018 )."
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"In addition, sodium channel dysfunction caused by mutations in the SCN5A gene, encoding the major sodium channel in heart, is associated with a number of arrhythmia syndromes."
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"The SCN5A-mediated sodium current gives rise to the rapid upstroke at the beginning of the action potential."
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"In this report, we reported a male infant patient with a history of recurrent VT, for whom whole-exome sequencing (WES) was used in early diagnoses of cardiac sodium channelopathies caused by SCN5A gene variants."
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