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Lori L Isom - One of the best experts on this subject based on the ideXlab platform.
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delayed maturation of gabaergic signaling in the scn1a and scn1b mouse models of dravet syndrome
Scientific Reports, 2019Co-Authors: Yukun Yuan, Heather A Omalley, Alexandra A. Bouza, Melissa A Smaldino, Jacob M Hull, Lori L IsomAbstract:Dravet syndrome (DS) is a catastrophic developmental and epileptic encephalopathy characterized by severe, pharmacoresistant seizures and the highest risk of Sudden Unexpected Death in Epilepsy (SUDEP) of all epilepsy syndromes. Here, we investigated the time course of maturation of neuronal GABAergic signaling in the Scn1b−/− and Scn1a+/− mouse models of DS. We found that GABAergic signaling remains immature in both DS models, with a depolarized reversal potential for GABAA-evoked currents compared to wildtype in the third postnatal week. Treatment of Scn1b−/− mice with bumetanide resulted in a delay in SUDEP onset compared to controls in a subset of mice, without prevention of seizure activity or amelioration of failure to thrive. We propose that delayed maturation of GABAergic signaling may contribute to epileptogenesis in SCN1B- and SCN1A-linked DS. Thus, targeting the polarity of GABAergic signaling in brain may be an effective therapeutic strategy to reduce SUDEP risk in DS.
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scn1b deletion leads to increased tetrodotoxin sensitive sodium current altered intracellular calcium homeostasis and arrhythmias in murine hearts
The Journal of Physiology, 2015Co-Authors: Heather A Omalley, David S Auerbach, Monique Foster, William A Coetzee, Glenn I Fishman, Mingliang Zhang, José Jalife, Chunling Chen, Akshay Shekhar, Lori L IsomAbstract:Na + current (INa) is determined not only by the properties of the pore-forming voltage-gated Na + channel (VGSC) α subunit, but also by the integrated function of a molecular aggregate (the VGSC complex) that includes the VGSC β subunit family. Mutations or rare variantsinScn1b(encodingthe β1andβ1Bsubunits)havebeenassociatedwithvariousinherited arrhythmogenic syndromes, including cases of Brugada syndrome and sudden unexpected death in patients with epilepsy. Here, we have used Scn1b null mouse models to understand better the relation between Scn1b expression, and cardiac electrical function. Using a combination of macropatch and scanning ion conductance microscopy we show that loss of Scn1b in juvenile null animals resulted in increased tetrodotoxin-sensitive INa but only in the cell midsection, even beforefullT-tubuleformation;thelatteroccurredconcurrentwithincreasedmessageabundance for the neuronal Scn3a mRNA, suggesting increased abundance of tetrodotoxin-sensitive NaV1.3 protein and yet its exclusion from the region of the intercalated disc. Ventricular myocytes from cardiac-specific adult Scn1b null animals showed increased Scn3a message, prolonged action potential repolarization, presence of delayed after-depolarizations and triggered beats, delayed Ca 2+ transients and frequent spontaneous Ca 2+ release events and at the whole heart level, increased susceptibility to polymorphic ventricular arrhythmias. Most alterations in Ca 2+
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na channel β subunits overachievers of the ion channel family
Frontiers in Pharmacology, 2011Co-Authors: William J. Brackenbury, Lori L IsomAbstract:Voltage gated Na+ channels (VGSCs) in mammals contain a pore-forming α subunit and one or more β subunits. There are five mammalian β subunits in total: β1, β1B, β2, β3, and β4, encoded by four genes: SCN1B-SCN4B. With the exception of the SCN1B splice variant, β1B, the β subunits are type I topology transmembrane proteins. In contrast, β1B lacks a transmembrane domain and is a secreted protein. A growing body of work shows that VGSC β subunits are multifunctional. While they do not form the ion channel pore, β subunits alter gating, voltage-dependence, and kinetics of VGSC α subunits and thus regulate cellular excitability in vivo. In addition to their roles in channel modulation, β subunits are members of the immunoglobulin (Ig) superfamily of cell adhesion molecules (CAMs) and regulate cell adhesion and migration. β subunits are also substrates for sequential proteolytic cleavage by secretases. An example of the multifunctional nature of β subunits is β1, encoded by SCN1B, that plays a critical role in neuronal migration and pathfinding during brain development, and whose function is dependent on Na+ current and γ-secretase activity. Functional deletion of SCN1B results in Dravet Syndrome, a severe and intractable pediatric epileptic encephalopathy. β subunits are emerging as key players in a wide variety of pathophysiologies, including epilepsy, cardiac arrhythmia, multiple sclerosis, Huntington’s disease, neuropsychiatric disorders, neuropathic and inflammatory pain, and cancer. β subunits mediate multiple signaling pathways on different timescales, regulating electrical excitability, adhesion, migration, pathfinding, and transcription. Importantly, some β subunit functions may operate independent of α subunits. Thus, β subunits perform critical roles during development and disease. As such, they may prove useful in disease diagnosis and therapy.
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na channel scn1b gene regulates dorsal root ganglion nociceptor excitability in vivo
Journal of Biological Chemistry, 2011Co-Authors: Luis F Lopezsantiago, William J. Brackenbury, Chunling Chen, Lori L IsomAbstract:Nociceptive dorsal root ganglion (DRG) neurons express tetrodotoxin-sensitive (TTX-S) and -resistant (TTX-R) Na+ current (INa) mediated by voltage-gated Na+ channels (VGSCs). In nociceptive DRG neurons, VGSC β2 subunits, encoded by Scn2b, selectively regulate TTX-S α subunit mRNA and protein expression, ultimately resulting in changes in pain sensitivity. We hypothesized that VGSCs in nociceptive DRG neurons may also be regulated by β1 subunits, encoded by Scn1b. Scn1b null mice are models of Dravet Syndrome, a severe pediatric encephalopathy. Many physiological effects of Scn1b deletion on CNS neurons have been described. In contrast, little is known about the role of Scn1b in peripheral neurons in vivo. Here we demonstrate that Scn1b null DRG neurons exhibit a depolarizing shift in the voltage dependence of TTX-S INa inactivation, reduced persistent TTX-R INa, a prolonged rate of recovery of TTX-R INa from inactivation, and reduced cell surface expression of Nav1.9 compared with their WT littermates. Investigation of action potential firing shows that Scn1b null DRG neurons are hyperexcitable compared with WT. Consistent with this, transient outward K+ current (Ito) is significantly reduced in null DRG neurons. We conclude that Scn1b regulates the electrical excitability of nociceptive DRG neurons in vivo by modulating both INa and IK.
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floxed allele for conditional inactivation of the voltage gated sodium channel β1 subunit scn1b
Genesis, 2007Co-Authors: Chunling Chen, Travis L Dickendesher, Nobuyuki Nukina, Haruko Miyazaki, Fumitaka Oyama, Lori L IsomAbstract:The voltage-gated sodium channel gene Scn1b encodes the auxiliary subunit β1, which is widely distributed in neurons and glia of the central and peripheral nervous systems, cardiac myocytes, skeletal muscle myocytes, and neuroendocrine cells. We showed previously that the Scn1b null mutation results in a complex and severe phenotype that includes retarded growth, seizures, ataxia, and death by postnatal day 21. We generated a floxed allele of Scn1b by inserting loxP sites surrounding the second coding exon. Ubiquitous deletion of the floxed exon by Cre recombinase using CMV-Cre-transgenic mice produced the Scn1bdel allele. The null phenotype of Scn1bdel homozygotes is indistinguishable from that of Scn1b nulls and confirms the invivo inactivation of Scn1b. Conditional inactivation ofthe floxed allele will make it possible to circumvent the lethality that results from complete loss of this gene, such that the physiological role of Scn1b in specific cell types and/or specific developmental time points can be investigated. genesis 45:547–553, 2007. © 2007 Wiley-Liss, Inc.
Jennifer A Kearney - One of the best experts on this subject based on the ideXlab platform.
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scn3a deficiency associated with increased seizure susceptibility
Neurobiology of Disease, 2017Co-Authors: Tyra Lamar, Andrew Escayg, Jennifer C Wong, Stacey B B Dutton, Benjamin S Jorge, Milen Velinov, Jeffrey D Calhoun, Carlos G. Vanoye, Jennifer A KearneyAbstract:Abstract Mutations in voltage-gated sodium channels expressed highly in the brain (SCN1A, SCN2A, SCN3A, and SCN8A) are responsible for an increasing number of epilepsy syndromes. In particular, mutations in the SCN3A gene, encoding the pore-forming Nav1.3 α subunit, have been identified in patients with focal epilepsy. Biophysical characterization of epilepsy-associated SCN3A variants suggests that both gain- and loss-of-function SCN3A mutations may lead to increased seizure susceptibility. In this report, we identified a novel SCN3A variant (L247P) by whole exome sequencing of a child with focal epilepsy, developmental delay, and autonomic nervous system dysfunction. Voltage clamp analysis showed no detectable sodium current in a heterologous expression system expressing the SCN3A-L247P variant. Furthermore, cell surface biotinylation demonstrated a reduction in the amount of SCN3A-L247P at the cell surface, suggesting the SCN3A-L247P variant is a trafficking-deficient mutant. To further explore the possible clinical consequences of reduced SCN3A activity, we investigated the effect of a hypomorphic Scn3a allele (Scn3aHyp) on seizure susceptibility and behavior using a gene trap mouse line. Heterozygous Scn3a mutant mice (Scn3a+/Hyp) did not exhibit spontaneous seizures nor were they susceptible to hyperthermia-induced seizures. However, they displayed increased susceptibility to electroconvulsive (6 Hz) and chemiconvulsive (flurothyl and kainic acid) induced seizures. Scn3a+/Hyp mice also exhibited deficits in locomotor activity and motor learning. Taken together, these results provide evidence that loss-of-function of SCN3A caused by reduced protein expression or deficient trafficking to the plasma membrane may contribute to increased seizure susceptibility.
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novel scn3a variants associated with focal epilepsy in children
Neurobiology of Disease, 2014Co-Authors: Carlos G. Vanoye, Katherine D Holland, Christina A Gurnett, Alfred L George, Jennifer A KearneyAbstract:Voltage-gated sodium (NaV) channels are essential for initiating and propagating action potentials in the brain. More than 800 mutations in genes encoding neuronal NaV channels including SCN1A and SCN2A have been associated with human epilepsy. Only one epilepsy-associated mutation has been identified in SCN3A encoding the NaV1.3 neuronal sodium channel. We performed a genetic screen of pediatric patients with focal epilepsy of unknown cause and identified four novel SCN3A missense variants: R357Q, D766N, E1111K and M1323V. We determined the functional consequences of these variants along with the previously reported K354Q mutation using heterologously expressed human NaV1.3. Functional defects were heterogeneous among the variants. The most severely affected was R357Q, which had a significantly smaller current density and slower activation than the wild-type (WT) channel as well as depolarized voltage dependences of activation and inactivation. Also notable was E1111K, which evoked a significantly greater level of persistent sodium current than WT channels. Interestingly, a common feature shared by all variant channels was increased current activation in response to depolarizing voltage ramps revealing a functional property consistent with conferring neuronal hyper-excitability. Discovery of a common biophysical defect among variants identified in unrelated pediatric epilepsy patients suggests that SCN3A may contribute to neuronal hyperexcitability and epilepsy.
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mutation of sodium channel scn3a in a patient with cryptogenic pediatric partial epilepsy
Neuroscience Letters, 2008Co-Authors: Katherine D Holland, Gerri Buck, John R Blankston, Ian W Glaaser, Robert S Kass, Mehdi Keddache, Tracy A Glauser, Jennifer A Kearney, Miriam H MeislerAbstract:Mutations in the sodium channel genes SCN1A and SCN2A have been identified in monogenic childhood epilepsies, but SCN3A has not previously been investigated as a candidate gene for epilepsy. We screened a consecutive cohort of 18 children with cryptogenic partial epilepsy that was classified as pharmacoresistant because of nonresponse to carbamazepine or oxcarbazepine, antiepileptic drugs that bind sodium channels. The novel coding variant SCN3A-K354Q was identified in one patient and was not present in 295 neurological normal controls. Twelve novel SNPs were also detected. K354Q alters an evolutionarily conserved amino acid in the pore domain of SCN3A. Functional analysis of this mutation in the backbone of the closely related gene SCN5A demonstrated an increase in persistent current that is similar in magnitude to epileptogenic mutations of SCN1A and SCN2A. This observation of a potentially pathogenic mutation of SCN3A (Nav1.3) indicates that this gene should be further evaluated for its contribution to childhood epilepsy.
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mutation of sodium channel scn3a in a patient with cryptogenic pediatric partial epilepsy
Neuroscience Letters, 2008Co-Authors: Katherine D Holland, Gerri Buck, John R Blankston, Ian W Glaaser, Robert S Kass, Mehdi Keddache, Tracy A Glauser, Jennifer A Kearney, Miriam H MeislerAbstract:Mutations in the sodium channel genes SCN1A and SCN2A have been identified in monogenic childhood epilepsies, but SCN3A has not previously been investigated as a candidate gene for epilepsy. We screened a consecutive cohort of 18 children with cryptogenic partial epilepsy that was classified as pharmacoresistant because of nonresponse to carbamazepine or oxcarbazepine, antiepileptic drugs that bind sodium channels. The novel coding variant SCN3A-K354Q was identified in one patient and was not present in 295 neurological normal controls. Twelve novel SNPs were also detected. K354Q substitutes glutamine for an evolutionarily conserved lysine residue in the pore domain of SCN3A. Functional analysis of this mutation in the backbone of the closely related gene SCN5A demonstrated an increase in persistent current that is similar in magnitude to epileptogenic mutations of SCN1A and SCN2A. This observation of a potentially pathogenic mutation of SCN3A (Nav1.3) indicates that this gene should be further evaluated for its contribution to childhood epilepsy.
Miriam H Meisler - One of the best experts on this subject based on the ideXlab platform.
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mutation of sodium channel scn3a in a patient with cryptogenic pediatric partial epilepsy
Neuroscience Letters, 2008Co-Authors: Katherine D Holland, Gerri Buck, John R Blankston, Ian W Glaaser, Robert S Kass, Mehdi Keddache, Tracy A Glauser, Jennifer A Kearney, Miriam H MeislerAbstract:Mutations in the sodium channel genes SCN1A and SCN2A have been identified in monogenic childhood epilepsies, but SCN3A has not previously been investigated as a candidate gene for epilepsy. We screened a consecutive cohort of 18 children with cryptogenic partial epilepsy that was classified as pharmacoresistant because of nonresponse to carbamazepine or oxcarbazepine, antiepileptic drugs that bind sodium channels. The novel coding variant SCN3A-K354Q was identified in one patient and was not present in 295 neurological normal controls. Twelve novel SNPs were also detected. K354Q alters an evolutionarily conserved amino acid in the pore domain of SCN3A. Functional analysis of this mutation in the backbone of the closely related gene SCN5A demonstrated an increase in persistent current that is similar in magnitude to epileptogenic mutations of SCN1A and SCN2A. This observation of a potentially pathogenic mutation of SCN3A (Nav1.3) indicates that this gene should be further evaluated for its contribution to childhood epilepsy.
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mutation of sodium channel scn3a in a patient with cryptogenic pediatric partial epilepsy
Neuroscience Letters, 2008Co-Authors: Katherine D Holland, Gerri Buck, John R Blankston, Ian W Glaaser, Robert S Kass, Mehdi Keddache, Tracy A Glauser, Jennifer A Kearney, Miriam H MeislerAbstract:Mutations in the sodium channel genes SCN1A and SCN2A have been identified in monogenic childhood epilepsies, but SCN3A has not previously been investigated as a candidate gene for epilepsy. We screened a consecutive cohort of 18 children with cryptogenic partial epilepsy that was classified as pharmacoresistant because of nonresponse to carbamazepine or oxcarbazepine, antiepileptic drugs that bind sodium channels. The novel coding variant SCN3A-K354Q was identified in one patient and was not present in 295 neurological normal controls. Twelve novel SNPs were also detected. K354Q substitutes glutamine for an evolutionarily conserved lysine residue in the pore domain of SCN3A. Functional analysis of this mutation in the backbone of the closely related gene SCN5A demonstrated an increase in persistent current that is similar in magnitude to epileptogenic mutations of SCN1A and SCN2A. This observation of a potentially pathogenic mutation of SCN3A (Nav1.3) indicates that this gene should be further evaluated for its contribution to childhood epilepsy.
Katherine D Holland - One of the best experts on this subject based on the ideXlab platform.
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novel scn3a variants associated with focal epilepsy in children
Neurobiology of Disease, 2014Co-Authors: Carlos G. Vanoye, Katherine D Holland, Christina A Gurnett, Alfred L George, Jennifer A KearneyAbstract:Voltage-gated sodium (NaV) channels are essential for initiating and propagating action potentials in the brain. More than 800 mutations in genes encoding neuronal NaV channels including SCN1A and SCN2A have been associated with human epilepsy. Only one epilepsy-associated mutation has been identified in SCN3A encoding the NaV1.3 neuronal sodium channel. We performed a genetic screen of pediatric patients with focal epilepsy of unknown cause and identified four novel SCN3A missense variants: R357Q, D766N, E1111K and M1323V. We determined the functional consequences of these variants along with the previously reported K354Q mutation using heterologously expressed human NaV1.3. Functional defects were heterogeneous among the variants. The most severely affected was R357Q, which had a significantly smaller current density and slower activation than the wild-type (WT) channel as well as depolarized voltage dependences of activation and inactivation. Also notable was E1111K, which evoked a significantly greater level of persistent sodium current than WT channels. Interestingly, a common feature shared by all variant channels was increased current activation in response to depolarizing voltage ramps revealing a functional property consistent with conferring neuronal hyper-excitability. Discovery of a common biophysical defect among variants identified in unrelated pediatric epilepsy patients suggests that SCN3A may contribute to neuronal hyperexcitability and epilepsy.
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mutation of sodium channel scn3a in a patient with cryptogenic pediatric partial epilepsy
Neuroscience Letters, 2008Co-Authors: Katherine D Holland, Gerri Buck, John R Blankston, Ian W Glaaser, Robert S Kass, Mehdi Keddache, Tracy A Glauser, Jennifer A Kearney, Miriam H MeislerAbstract:Mutations in the sodium channel genes SCN1A and SCN2A have been identified in monogenic childhood epilepsies, but SCN3A has not previously been investigated as a candidate gene for epilepsy. We screened a consecutive cohort of 18 children with cryptogenic partial epilepsy that was classified as pharmacoresistant because of nonresponse to carbamazepine or oxcarbazepine, antiepileptic drugs that bind sodium channels. The novel coding variant SCN3A-K354Q was identified in one patient and was not present in 295 neurological normal controls. Twelve novel SNPs were also detected. K354Q alters an evolutionarily conserved amino acid in the pore domain of SCN3A. Functional analysis of this mutation in the backbone of the closely related gene SCN5A demonstrated an increase in persistent current that is similar in magnitude to epileptogenic mutations of SCN1A and SCN2A. This observation of a potentially pathogenic mutation of SCN3A (Nav1.3) indicates that this gene should be further evaluated for its contribution to childhood epilepsy.
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mutation of sodium channel scn3a in a patient with cryptogenic pediatric partial epilepsy
Neuroscience Letters, 2008Co-Authors: Katherine D Holland, Gerri Buck, John R Blankston, Ian W Glaaser, Robert S Kass, Mehdi Keddache, Tracy A Glauser, Jennifer A Kearney, Miriam H MeislerAbstract:Mutations in the sodium channel genes SCN1A and SCN2A have been identified in monogenic childhood epilepsies, but SCN3A has not previously been investigated as a candidate gene for epilepsy. We screened a consecutive cohort of 18 children with cryptogenic partial epilepsy that was classified as pharmacoresistant because of nonresponse to carbamazepine or oxcarbazepine, antiepileptic drugs that bind sodium channels. The novel coding variant SCN3A-K354Q was identified in one patient and was not present in 295 neurological normal controls. Twelve novel SNPs were also detected. K354Q substitutes glutamine for an evolutionarily conserved lysine residue in the pore domain of SCN3A. Functional analysis of this mutation in the backbone of the closely related gene SCN5A demonstrated an increase in persistent current that is similar in magnitude to epileptogenic mutations of SCN1A and SCN2A. This observation of a potentially pathogenic mutation of SCN3A (Nav1.3) indicates that this gene should be further evaluated for its contribution to childhood epilepsy.
Parvez Hakim - One of the best experts on this subject based on the ideXlab platform.
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effects of flecainide and quinidine on action potential and ventricular arrhythmogenic properties in SCN3B knockout mice
Clinical and Experimental Pharmacology and Physiology, 2010Co-Authors: Parvez Hakim, Rosemary Thresher, Andrew A Grace, Christopher L H HuangAbstract:1. Flecainide and quinidine exert contrasting pro-arrhythmic and anti-arrhythmic effects in mouse hearts containing the loss-of-function, Scn5a(+/-), and the gain-of-function, Scn5a(+/DeltaKPQ), mutations in their sodium channel alpha-subunits. 2. The following properties were accordingly compared in wild-type and SCN3B(-/-) hearts modelling modifications in the beta-subunit, before and after introduction of either agent: (i) ventricular arrhythmogenecity and effective refractory periods (VERP) in response to programmed electrical stimulation (PES); (ii) monophasic action potential waveforms recorded from the left ventricular epicardium and endocardium; (iii) action potential durations (APD) obtained from the monophasic action potentials; and (iv) critical intervals derived from the APD and VERP values. 3. Ventricular tachycardia was induced by PES in 11 out of 15 SCN3B(-/-) hearts and 0 out of 17 wild-type hearts. This incidence was reduced to three out of eight SCN3B(-/-) hearts but increased to three out of eight wild-type hearts with flecainide. 4. Arrhythmogenic incidence was reduced to two out of eight SCN3B(-/-) hearts and remained at 0 out of eight wild-type hearts in the presence of quinidine. 5. Ventricular effective refractory periods were prolonged and endocardial and epicardial APD shortened, resulting in negative critical intervals in both SCN3B(-/-) and wild-type hearts treated by either flecainide or quinidine. Nevertheless, endocardial APD remained consistently longer than epicardial APD, leaving similar, positive endocardial-epicardial, differences, DeltaAPD, in treated and untreated SCN3B(-/-) and wild-type hearts. 6. It is concluded that both flecainide and quinidine exert anti-arrhythmogenic effects in SCN3B(-/-) hearts, doing so through modifying VERP rather than DeltaAPD, in contrast to their differing effects in Scn5a(+/-) and Scn5a(+/DeltaKPQ) hearts.
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SCN3B knockout mice exhibit abnormal sino atrial and cardiac conduction properties
Acta Physiologica, 2010Co-Authors: Parvez Hakim, Antony P Jackson, Nicola Brice, Rosemary Thresher, Jason Lawrence, Yanmin Zhang, Andrew A Grace, C L H HuangAbstract:Aim: In contrast to extensive reports on the roles of Nav1.5 α-subunits, there have been few studies associating the β-subunits with cardiac arrhythmogenesis. We investigated the sino-atrial and conduction properties in the hearts of SCN3B−/− mice. Methods: The following properties were compared in the hearts of wild-type (WT) and SCN3B−/− mice: (1) mRNA expression levels of SCN3B, Scn1b and Scn5a in atrial tissue. (2) Expression of the β3 protein in isolated cardiac myocytes. (3) Electrocardiographic recordings in intact anaesthetized preparations. (4) Bipolar electrogram recordings from the atria of spontaneously beating and electrically stimulated Langendorff-perfused hearts. Results: SCN3B mRNA was expressed in the atria of WT but not SCN3B−/− hearts. This was in contrast to similar expression levels of Scn1b and Scn5a mRNA. Immunofluorescence experiments confirmed that the β3 protein was expressed in WT and absent in SCN3B−/− cardiac myocytes. Lead I electrocardiograms from SCN3B−/− mice showed slower heart rates, longer P wave durations and prolonged PR intervals than WT hearts. Spontaneously beating Langendorff-perfused SCN3B−/− hearts demonstrated both abnormal atrial electrophysiological properties and evidence of partial or complete dissociation of atrial and ventricular activity. Atrial burst pacing protocols induced atrial tachycardia and fibrillation in all SCN3B−/− but hardly any WT hearts. SCN3B−/− hearts also demonstrated significantly longer sinus node recovery times than WT hearts. Conclusion: These findings demonstrate, for the first time, that a deficiency in SCN3B results in significant atrial electrophysiological and intracardiac conduction abnormalities, complementing the changes in ventricular electrophysiology reported on an earlier occasion.
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SCN3B knockout mice exhibit abnormal ventricular electrophysiological properties
Progress in Biophysics & Molecular Biology, 2008Co-Authors: Parvez Hakim, Nicola Brice, Rosemary Thresher, Jason Lawrence, Andrew A Grace, Iman S Gurung, Thomas Holm Pedersen, Christopher HuangAbstract:We report for the first time abnormalities in cardiac ventricular electrophysiology in a genetically modified murine model lacking the SCN3B gene (SCN3B−/−). SCN3B−/− mice were created by homologous recombination in embryonic stem (ES) cells. RT-PCR analysis confirmed that SCN3B mRNA was expressed in the ventricles of wild-type (WT) hearts but was absent in the SCN3B−/− hearts. These hearts also showed increased expression levels of Scn1b mRNA in both ventricles and Scn5a mRNA in the right ventricles compared to findings in WT hearts. Scn1b and Scn5a mRNA was expressed at higher levels in the left than in the right ventricles of both SCN3B−/− and WT hearts. Bipolar electrogram and monophasic action potential recordings from the ventricles of Langendorff-perfused SCN3B−/− hearts demonstrated significantly shorter ventricular effective refractory periods (VERPs), larger ratios of electrogram duration obtained at the shortest and longest S1–S2 intervals, and ventricular tachycardias (VTs) induced by programmed electrical stimulation. Such arrhythmogenesis took the form of either monomorphic or polymorphic VT. Despite shorter action potential durations (APDs) in both the endocardium and epicardium, SCN3B−/− hearts showed ΔAPD90 values that remained similar to those shown in WT hearts. The whole-cell patch-clamp technique applied to ventricular myocytes isolated from SCN3B−/− hearts demonstrated reduced peak Na+ current densities and inactivation curves that were shifted in the negative direction, relative to those shown in WT myocytes. Together, these findings associate the lack of the SCN3B gene with arrhythmic tendencies in intact perfused hearts and electrophysiological features similar to those in Scn5a+/− hearts.