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Miriam H Meisler - One of the best experts on this subject based on the ideXlab platform.
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Sodium Channel SCN8A (Nav1.6): properties and de novo mutations in epileptic encephalopathy and intellectual disability
Frontiers in Genetics, 2013Co-Authors: Janelle E. O’brien, Miriam H MeislerAbstract:The Sodium Channel Nav1.6, encoded by the gene SCN8A, is one of the major voltage-gated Channels in human brain. The sequences of Sodium Channels have been highly conserved during evolution, and minor changes in biophysical properties can have a major impact in vivo. Insight into the role of Nav1.6 has come from analysis of spontaneous and induced mutations of mouse Scn8a during the past 18 years. Only within the past year has the role of SCN8A in human disease become apparent from whole exome and genome sequences of patients with sporadic disease. Unique features of Nav1.6 include its contribution to persistent current, resurgent current, repetitive neuronal firing, and subcellular localization at the axon initial segment and nodes of Ranvier. Loss of Nav1.6 activity results in reduced neuronal excitability, while gain-of-function mutations can increase neuronal excitability. Mouse Scn8a (med) mutants exhibit movement disorders including ataxia, tremor and dystonia. Thus far, more than ten human de novo mutations have been identified in patients with two types of disorders, epileptic encephalopathy and intellectual disability. We review these human mutations as well as the unique features of Nav1.6 that contribute to its role in determining neuronal excitability in vivo. A supplemental figure illustrating the positions of amino acid residues within the 4 domains and 24 transmembrane segments of Nav1.6 is provided to facilitate the location of novel mutations within the Channel protein.
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interaction of voltage gated Sodium Channel Nav1.6 scn8a with microtubule associated protein map1b
Journal of Biological Chemistry, 2012Co-Authors: Janelle E Obrien, Lisa M Sharkey, Christina N Vallianatos, Chongyang Han, Julie C Blossom, Stephen G Waxman, Sulayman D Dibhajj, Miriam H MeislerAbstract:Abstract The mechanism by which voltage-gated Sodium Channels are trafficked to the surface of neurons is not well understood. Our previous work implicated the cytoplasmic N terminus of the Sodium Channel Nav1.6 in this process. We report that the N terminus plus the first transmembrane segment (residues 1–153) is sufficient to direct a reporter to the cell surface. To identify proteins that interact with the 117-residue N-terminal domain, we carried out a yeast two-hybrid screen of a mouse brain cDNA library. Three clones containing overlapping portions of the light chain of microtubule-associated protein Map1b (Mtap1b) were recovered from the screen. Interaction between endogenous Nav1.6 Channels and Map1b in mouse brain was confirmed by co-immunoprecipitation. Map1b did not interact with the N terminus of the related Channel Nav1.1. Alanine-scanning mutagenesis of the Nav1.6 N terminus demonstrated that residues 77–80 (VAVP) contribute to interaction with Map1b. Co-expression of Nav1.6 with Map1b in neuronal cell line ND7/23 resulted in a 50% increase in current density, demonstrating a functional role for this interaction. Mutation of the Map1b binding site of Nav1.6 prevented generation of Sodium current in transfected cells. The data indicate that Map1b facilitates trafficking of Nav1.6 to the neuronal cell surface.
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a null mutation of the neuronal Sodium Channel Nav1.6 disrupts action potential propagation and excitation contraction coupling in the mouse heart
The FASEB Journal, 2012Co-Authors: Sami F Noujaim, Miriam H Meisler, Kuljeet Kaur, Michelle L Milstein, Julie M Jones, Philip B Furspan, Daniel Jiang, David S Auerbach, Todd J Herron, Jose JalifeAbstract:Evidence supports the expression of brain-type Sodium Channels in the heart. Their functional role, however, remains controversial. We used global Nav1.6-null mice to test the hypothesis that Nav1.6 contributes to the maintenance of propagation in the myocardium and to excitation-contraction (EC) coupling. We demonstrated expression of transcripts encoding full-length Nav1.6 in isolated ventricular myocytes and confirmed the striated pattern of Nav1.6 fluorescence in myocytes. On the ECG, the PR and QRS intervals were prolonged in the null mice, and the Ca2+ transients were longer in the null cells. Under patch clamping, at holding potential (HP) = −120 mV, the peak INa was similar in both phenotypes. However, at HP = −70 mV, the peak INa was smaller in the nulls. In optical mapping, at 4 mM [K+]o, 17 null hearts showed slight (7%) reduction of ventricular conduction velocity (CV) compared to 16 wild-type hearts. At 12 mM [K+]o, CV was 25% slower in a subset of 9 null vs. 9 wild-type hearts. These results highlight the importance of neuronal Sodium Channels in the heart, whereby Nav1.6 participates in EC coupling, and represents an intrinsic depolarizing reserve that contributes to excitation.—Noujaim, S. F., Kaur, K., Milstein, M., Jones, J. M., Furspan, P., Jiang, D., Auerbach, D. S., Herron, T., Meisler, M. H., Jalife, J. A null mutation of the neuronal Sodium Channel Nav1.6 disrupts action potential propagation and excitation-contraction coupling in the mouse heart.
Del'guidice Thomas - One of the best experts on this subject based on the ideXlab platform.
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Recherche de nouvelles cibles pharmacologiques en psychiatrie par l'étude des monoamines - approches neuropsychopharmacologiques de la cognition et des émotions chez l'animal
Université Laval, 2014Co-Authors: Del'guidice ThomasAbstract:La dopamine, la sérotonine et la noradrénaline sont des neurotransmetteurs dits monoaminergiques. Connus pour leur rôle dans de nombreuses fonctions cognitives, émotionnels et motrices, les récepteurs, transporteurs et autres médiateurs cellulaires des monoamines sont les cibles principales des agents pharmacologiques utilisés en psychiatrie et appelés psychotropes. Dans notre laboratoire, nous appréhendons de manière multidisciplinaire le rôle de ces neurotransmetteurs sur le comportement et la biochimie du cerveau, ainsi que l’impact des psychotropes sur les cibles cellulaires monoaminergiques susceptibles de réguler les comportements cognitifs et émotionnels chez la souris. Le test comportemental automatisé appelé H-maze, nous a permis de mesurer l’impact cognitif de plusieurs dérèglements monoaminergiques chez des souris génétiquement modifiées. Des souris déficientes en sérotonine (Tph2-KI) ou hyperdopaminergiques (DAT-KO) présentent de profondes altérations des fonctions exécutives. Grâce à la complexité du paradigme présenté dans le H-maze, nous pouvons modéliser des symptômes cognitifs observés chez l’homme (ex : persévération dans l’erreur) et restaurer de manière sélective des facultés d’apprentissage indépendamment d’autres fonctions cérébrales comme la motricité. La stimulation pharmacologique du récepteur à sérotonine 5HT2C chez la souris Tph2-KIet le blocage du transporteur de la noradrénaline NET chez la souris DAT-KO ont permis d’abolir les déficits cognitifs observés. En parallèle, nous avons étudié les fonctions de plusieurs acteurs intracellulaires régulés par les monoamines et découvert un nouveau mode d’action commun aux psychotropes appelés stabilisateurs de l’humeur. Ces derniers, le lithium, le valproate et la lamotrigine, régulent plusieurs comportements émotionnels chez la souris via une voie de signalisation dopaminergique appelée Akt/GSK3 sous la dépendance de la protéine βArrestine 2. De plus, nous montrons pour la première fois que cette voie est orchestrée par la formation d’un complexe protéique entre le récepteur D2 et le canal sodique Nav1.6, et que cette interaction serait un mécanisme cellulaire directement ciblé par le valproate et la lamotrigine. Enfin, nous avons découvert un nouveau substrat de GSK3, la protéine du X-fragile FXR1, qui pourrait participer aux effets antidépresseurs et anxiolytiques des stabilisateurs de l’humeur. Nous espérons que ces découvertes pourront contribuer au développement d’agents pharmacologiques plus efficaces et dénués d’effets secondaires.Dopamine, serotonin and norepinephrine are monoaminergic neurotransmitters. Receptors, transporters and others monoamines compounds are involved in several brain functions such as cognition, emotions and locomotion, and are targeted by psychotropic drugs. In our research center, we focus on multidisciplinary approaches to better understand the role of monoamines on brain-regulated behavioral and biochemical processes, and on the impact of these agents on the monoamine cellular targets involved in the regulation of cognitive and emotional behaviors in mice. Using the automated behavioral test named olfactory H-maze, we measured the cognitive impact of several monoaminergic metabolic changes in mutant mice. Serotonin deficient (Tph2-KI) or hyperdopaminergic (DAT-KO) mice showed severe cognitive deficits. Thanks to the complexity of the H-maze, we were able to rescue learning and cognitive flexibility in these mice independently from others brain functions like motricity, and by targeting several extracellular monoaminergic substrates, like the serotonin 5HT2C receptor and the norepinephrine transporter. Furthermore, we investigate the cellular functions of several monoamines-regulated intracellular compounds and identified a new common action mode of psychotropic drugs mood stabilizers. We showed that lithium, valproate and lamotrigine may regulate several emotional behaviors by involving the Akt/GSK3 signaling pathway and the multifunctional scaffolding protein βarrestin 2. Thus, we show for the first time that this signaling cascade may be regulated by the formation of a protein complex composed by the D2 receptor and the voltage-gated Sodium Channel Nav1.6. This interaction would be a mechanism targeted by mood stabilizers valproate and lamotrigine. Finally, we found a new common substrate of GSK3 for these three mood stabilizers, the fragile X-related protein 1 (FXR1), which may participate to the regulation of mood by these agents. We hope that our works will lead to new research avenues and, in the future, to the development of more efficacy psychotropic drugs without aversive side effects.Tableau d'honneur de la FÉS
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Recherche de nouvelles cibles pharmacologiques en psychiatrie par l'étude des monoamines : approches neuropsychopharmacologiques de la cognition et des émotions chez l'animal
Bibliotheque de l' Universite Laval, 2013Co-Authors: Del'guidice ThomasAbstract:Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2013-2014.La dopamine, la sérotonine et la noradrénaline sont des neurotransmetteurs dits monoaminergiques. Connus pour leur rôle dans de nombreuses fonctions cognitives, émotionnels et motrices, les récepteurs, transporteurs et autres médiateurs cellulaires des monoamines sont les cibles principales des agents pharmacologiques utilisés en psychiatrie et appelés psychotropes. Dans notre laboratoire, nous appréhendons de manière multidisciplinaire le rôle de ces neurotransmetteurs sur le comportement et la biochimie du cerveau, ainsi que l’impact des psychotropes sur les cibles cellulaires monoaminergiques susceptibles de réguler les comportements cognitifs et émotionnels chez la souris. Le test comportemental automatisé appelé H-maze, nous a permis de mesurer l’impact cognitif de plusieurs dérèglements monoaminergiques chez des souris génétiquement modifiées. Des souris déficientes en sérotonine (Tph2-KI) ou hyperdopaminergiques (DAT-KO) présentent de profondes altérations des fonctions exécutives. Grâce à la complexité du paradigme présenté dans le H-maze, nous pouvons modéliser des symptômes cognitifs observés chez l’homme (ex : persévération dans l’erreur) et restaurer de manière sélective des facultés d’apprentissage indépendamment d’autres fonctions cérébrales comme la motricité. La stimulation pharmacologique du récepteur à sérotonine 5HT2C chez la souris Tph2-KIet le blocage du transporteur de la noradrénaline NET chez la souris DAT-KO ont permis d’abolir les déficits cognitifs observés. En parallèle, nous avons étudié les fonctions de plusieurs acteurs intracellulaires régulés par les monoamines et découvert un nouveau mode d’action commun aux psychotropes appelés stabilisateurs de l’humeur. Ces derniers, le lithium, le valproate et la lamotrigine, régulent plusieurs comportements émotionnels chez la souris via une voie de signalisation dopaminergique appelée Akt/GSK3 sous la dépendance de la protéine βArrestine 2. De plus, nous montrons pour la première fois que cette voie est orchestrée par la formation d’un complexe protéique entre le récepteur D2 et le canal sodique Nav1.6, et que cette interaction serait un mécanisme cellulaire directement ciblé par le valproate et la lamotrigine. Enfin, nous avons découvert un nouveau substrat de GSK3, la protéine du X-fragile FXR1, qui pourrait participer aux effets antidépresseurs et anxiolytiques des stabilisateurs de l’humeur. Nous espérons que ces découvertes pourront contribuer au développement d’agents pharmacologiques plus efficaces et dénués d’effets secondaires.Dopamine, serotonin and norepinephrine are monoaminergic neurotransmitters. Receptors, transporters and others monoamines compounds are involved in several brain functions such as cognition, emotions and locomotion, and are targeted by psychotropic drugs. In our research center, we focus on multidisciplinary approaches to better understand the role of monoamines on brain-regulated behavioral and biochemical processes, and on the impact of these agents on the monoamine cellular targets involved in the regulation of cognitive and emotional behaviors in mice. Using the automated behavioral test named olfactory H-maze, we measured the cognitive impact of several monoaminergic metabolic changes in mutant mice. Serotonin deficient (Tph2-KI) or hyperdopaminergic (DAT-KO) mice showed severe cognitive deficits. Thanks to the complexity of the H-maze, we were able to rescue learning and cognitive flexibility in these mice independently from others brain functions like motricity, and by targeting several extracellular monoaminergic substrates, like the serotonin 5HT2C receptor and the norepinephrine transporter. Furthermore, we investigate the cellular functions of several monoamines-regulated intracellular compounds and identified a new common action mode of psychotropic drugs mood stabilizers. We showed that lithium, valproate and lamotrigine may regulate several emotional behaviors by involving the Akt/GSK3 signaling pathway and the multifunctional scaffolding protein βarrestin 2. Thus, we show for the first time that this signaling cascade may be regulated by the formation of a protein complex composed by the D2 receptor and the voltage-gated Sodium Channel Nav1.6. This interaction would be a mechanism targeted by mood stabilizers valproate and lamotrigine. Finally, we found a new common substrate of GSK3 for these three mood stabilizers, the fragile X-related protein 1 (FXR1), which may participate to the regulation of mood by these agents. We hope that our works will lead to new research avenues and, in the future, to the development of more efficacy psychotropic drugs without aversive side effects
Thomas Durek - One of the best experts on this subject based on the ideXlab platform.
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the e15r point mutation in scorpion toxin cn2 uncouples its depressant and excitatory activities on human Nav1.6
Journal of Medicinal Chemistry, 2018Co-Authors: Mathilde R Israel, Panumart Thongyoo, Jennifer R. Deuis, David J. Craik, Irina Vetter, Thomas DurekAbstract:We report the chemical synthesis of scorpion toxin Cn2, a potent and highly selective activator of the human voltage-gated Sodium Channel Nav1.6. In an attempt to decouple Channel activation from Channel binding, we also synthesized the first analogue of this toxin, Cn2[E15R]. This mutation caused uncoupling of the toxin's excitatory and depressant activities, effectively resulting in a Nav1.6 inhibitor. In agreement with the in vitro observations, Cn2[E15R] is antinociceptive in mouse models of Nav1.6-mediated pain.
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The E15R Point Mutation in Scorpion Toxin Cn2 Uncouples Its Depressant and Excitatory Activities on Human Nav1.6
2018Co-Authors: Mathilde R. Israel, Panumart Thongyoo, Jennifer R. Deuis, David J. Craik, Irina Vetter, Thomas DurekAbstract:We report the chemical synthesis of scorpion toxin Cn2, a potent and highly selective activator of the human voltage-gated Sodium Channel Nav1.6. In an attempt to decouple Channel activation from Channel binding, we also synthesized the first analogue of this toxin, Cn2[E15R]. This mutation caused uncoupling of the toxin’s excitatory and depressant activities, effectively resulting in a Nav1.6 inhibitor. In agreement with the in vitro observations, Cn2[E15R] is antinociceptive in mouse models of Nav1.6-mediated pain
Stephen G Waxman - One of the best experts on this subject based on the ideXlab platform.
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interaction of voltage gated Sodium Channel Nav1.6 scn8a with microtubule associated protein map1b
Journal of Biological Chemistry, 2012Co-Authors: Janelle E Obrien, Lisa M Sharkey, Christina N Vallianatos, Chongyang Han, Julie C Blossom, Stephen G Waxman, Sulayman D Dibhajj, Miriam H MeislerAbstract:Abstract The mechanism by which voltage-gated Sodium Channels are trafficked to the surface of neurons is not well understood. Our previous work implicated the cytoplasmic N terminus of the Sodium Channel Nav1.6 in this process. We report that the N terminus plus the first transmembrane segment (residues 1–153) is sufficient to direct a reporter to the cell surface. To identify proteins that interact with the 117-residue N-terminal domain, we carried out a yeast two-hybrid screen of a mouse brain cDNA library. Three clones containing overlapping portions of the light chain of microtubule-associated protein Map1b (Mtap1b) were recovered from the screen. Interaction between endogenous Nav1.6 Channels and Map1b in mouse brain was confirmed by co-immunoprecipitation. Map1b did not interact with the N terminus of the related Channel Nav1.1. Alanine-scanning mutagenesis of the Nav1.6 N terminus demonstrated that residues 77–80 (VAVP) contribute to interaction with Map1b. Co-expression of Nav1.6 with Map1b in neuronal cell line ND7/23 resulted in a 50% increase in current density, demonstrating a functional role for this interaction. Mutation of the Map1b binding site of Nav1.6 prevented generation of Sodium current in transfected cells. The data indicate that Map1b facilitates trafficking of Nav1.6 to the neuronal cell surface.
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Sodium Channel expression within chronic multiple sclerosis plaques
Journal of Neuropathology and Experimental Neurology, 2007Co-Authors: Joel A Black, Jia Newcombe, Bruce D Trapp, Stephen G WaxmanAbstract:Multiple sclerosis (MS) is characterized by focal destruction of myelin sheaths, gliotic scars, and axonal damage that contributes to the accumulation of nonremitting clinical deficits. Previous studies have demonstrated coexpression of Sodium Channel Nav1.6 and the Sodium-calcium exchanger (NCX), together with beta-amyloid precursor protein (beta-APP), a marker of axonal damage, in degenerating axons within acute MS lesions. Axonal degeneration is less frequent within chronic MS lesions than in acute plaques, although current evidence suggests that axonal loss in chronic lesions ("slow burn") is a major contributor to accumulating disability. It is not known, however, whether axonal degenerations in chronic and acute lesions share common mechanisms, despite radically differing extracellular milieus. In this study, the expression of Sodium Channels Nav1.2 and Nav1.6 and of NCX was examined in chronic MS plaques within the spinal cord. Nav1.2 immunostaining was not observed along demyelinated axons in chronic lesions but was expressed by scar and reactive astrocytes within the plaque. Nav1.6 immunoreactivity, which was intense at nodes of Ranvier in normal appearing white matter in the same sections, was present in approximately one-third of the demyelinated axons within these plaques in a patchy rather than continuous distribution. NCX was not detected in demyelinated axons within chronic lesions, although it was clearly present within the scar astrocytes surrounding the demyelinated axons. beta-APP accumulation occurred in a small percentage of axons within chronic lesions within the spinal cord, but beta-APP was not preferentially present in axons that expressed Nav1.6. These observations suggest that different mechanisms underlie axonal degeneration in acute and chronic MS lesions, with axonal injury occurring at sites of coexpression of Nav1.6 and NCX in acute lesions but independent of coexpression of these 2 molecules in chronic lesions.
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Sodium Channels contribute to microglia macrophage activation and function in eae and ms
Glia, 2005Co-Authors: Matthew J. Craner, Joel A Black, Jia Newcombe, Tina G Damarjian, Shujun Liu, Bryan C Hains, Louise M Cuzner, Stephen G WaxmanAbstract:Loss of axons is a major contributor to nonremitting deficits in the inflammatory demyelinating disease multiple sclerosis (MS). Based on biophysical studies showing that activity of axonal Sodium Channels can trigger axonal degeneration, recent studies have tested Sodium Channel-blocking drugs in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and have demonstrated a protective effect on axons. However, it is possible that, in addition to a direct effect on axons, Sodium Channel blockers may also interfere with inflammatory mechanisms. We therefore examined the novel hypothesis that Sodium Channels contribute to activation of microglia and macrophages in EAE and acute MS lesions. In this study, we demonstrate a robust increase of Sodium Channel Nav1.6 expression in activated microglia and macrophages in EAE and MS. We further demonstrate that treatment with the Sodium Channel blocker phenytoin ameliorates the inflammatory cell infiltrate in EAE by 75%. Supporting a role for Sodium Channels in microglial activation, we show that tetrodotoxin, a specific Sodium Channel blocker, reduces the phagocytic function of activated rat microglia by 40%. To further confirm a role of Nav1.6 in microglial activation, we examined the phagocytic capacity of microglia from med mice, which lack Nav1.6 Channels, and show a 65% reduction in phagocytic capacity compared with microglia from wildtype mice. Our findings indicate that Sodium Channels are important for activation and phagocytosis of microglia and macrophages in EAE and MS and suggest that, in addition to a direct neuroprotective effect on axons, Sodium Channel blockade may ameliorate neuroinflammatory disorders via anti-inflammatory mechanisms.
Mathilde R Israel - One of the best experts on this subject based on the ideXlab platform.
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the e15r point mutation in scorpion toxin cn2 uncouples its depressant and excitatory activities on human Nav1.6
Journal of Medicinal Chemistry, 2018Co-Authors: Mathilde R Israel, Panumart Thongyoo, Jennifer R. Deuis, David J. Craik, Irina Vetter, Thomas DurekAbstract:We report the chemical synthesis of scorpion toxin Cn2, a potent and highly selective activator of the human voltage-gated Sodium Channel Nav1.6. In an attempt to decouple Channel activation from Channel binding, we also synthesized the first analogue of this toxin, Cn2[E15R]. This mutation caused uncoupling of the toxin's excitatory and depressant activities, effectively resulting in a Nav1.6 inhibitor. In agreement with the in vitro observations, Cn2[E15R] is antinociceptive in mouse models of Nav1.6-mediated pain.