"These compounds were screened for their ability to block PrP formation in ScN2a cells, resulting in the identification of the inhibitor 2-amino-6-[(2-aminophenyl)thio]-4-(2-furyl)pyridine-3,5-dicarbonitrile (Cp-60), with an
of 18μM . Although Cp-60 is a relatively weak inhibitor of prion formation, chemical modification of the Cp-60 backbone may eventually produce a compound that potently binds to an unidentified cellular factor responsible for mediating dominant-negative inhibition of prion formation by specific polymorphic PrP alleles."
"Quinacrine, an antimalarial acridine derivative, has been shown to inhibit PrP formation in ScN2a cells with an
of 0.3–0.4μM . A comparative analysis using 24 structurally related acridine and phenothiazine derivatives revealed that the nitrogen atom at the 9 position of the tricyclic scaffold and the length and composition of the aliphatic side chain all contributed to inhibitory potency ."
"The most potent blocking Fab, D18, inhibits PrP formation in ScN2a cells at a concentration of 6nM, whereas R72, a different high-affinity anti-PrP Fab, fails to alter PrP levels at a >400nM concentration () ."
"To demonstrate specificity, radioactive binding to specific sites in crude extracts should not be displaceable by compounds such as quinacrine mustard or PcTS-Al, in accordance with the inability of these compounds to inhibit PrP formation in ScN2a cells."
"To investigate the efficacy of quinacrine enantiomers, we measured the inhibitory effect of these isomers on PrP(Sc) formation in ScN2a cells. (S)-quinacrine exhibited superior antiprion activity compared with (R)-quinacrine and two generic quinacrines that appear to be racemates."
"Even the 6-hydroxy BTA-1 derivative (also called PIB or 6-OH-BTA-1) inhibited PrPSc formation in ScN2a cells with an IC 50 in the nanomolar range; more importantly, it has been selected for the first human trial of a benzothiazole amyloid-imaging agent [ xref ]."
"By constructing a series of chimeric mouse (Mo)/SHaPrP genes, we developed an epitopically tagged functional variant of the MoPrP gene, which can efficiently form protease-resistant PrP molecules upon expression in ScN2a cells."
"Chronic exposure of ScN2a cells to low noncytotoxic concentrations of branched polyamines for 1 wk reduced PrP (Sc) to an undetectable level, a condition that persisted at least 3 wk after removal of the compound."
"We now demonstrate that exposure of ScN2a cells to 3 microg of PPI generation 4.0/ml for 4 weeks not only reduced PrP (Sc) to a level undetectable by Western blot but also eradicated prion infectivity as determined by a bioassay in mice."
"ScN2a and ScHaB cells in culture produce several PrP molecules with relative molecular masses of 26-35 kDa and proteinase K resistant cores of 19-29 kDa."
"One compound, termed Compound B (CmpdB) (XREF_FIG), had cellular EC 50 values of 60 pM in ScN2a cells and ~ 300 muM in two ScN2a cell lines overexpressing PrP."
"We found that incubation of ScN2a cells with a fibril peptide named P9, which comprises an intrinsic sequence of residues 167-184 of mouse PrP (C), significantly reduced the amount of PrP (Sc) in 24 hr."
"These compounds were screened for their ability to block PrP formation in ScN2a cells, resulting in the identification of the inhibitor 2-amino-6-[(2-aminophenyl)thio]-4-(2-furyl)pyridine-3,5-dicarbonitrile (Cp-60), with an
of 18μM . Although Cp-60 is a relatively weak inhibitor of prion formation, chemical modification of the Cp-60 backbone may eventually produce a compound that potently binds to an unidentified cellular factor responsible for mediating dominant-negative inhibition of prion formation by specific polymorphic PrP alleles."
"Quinacrine, an antimalarial acridine derivative, has been shown to inhibit PrP formation in ScN2a cells with an
of 0.3–0.4μM . A comparative analysis using 24 structurally related acridine and phenothiazine derivatives revealed that the nitrogen atom at the 9 position of the tricyclic scaffold and the length and composition of the aliphatic side chain all contributed to inhibitory potency ."
"The most potent blocking Fab, D18, inhibits PrP formation in ScN2a cells at a concentration of 6nM, whereas R72, a different high-affinity anti-PrP Fab, fails to alter PrP levels at a >400nM concentration () ."
"To demonstrate specificity, radioactive binding to specific sites in crude extracts should not be displaceable by compounds such as quinacrine mustard or PcTS-Al, in accordance with the inability of these compounds to inhibit PrP formation in ScN2a cells."
"To investigate the efficacy of quinacrine enantiomers, we measured the inhibitory effect of these isomers on PrP(Sc) formation in ScN2a cells. (S)-quinacrine exhibited superior antiprion activity compared with (R)-quinacrine and two generic quinacrines that appear to be racemates."
"Even the 6-hydroxy BTA-1 derivative (also called PIB or 6-OH-BTA-1) inhibited PrPSc formation in ScN2a cells with an IC 50 in the nanomolar range; more importantly, it has been selected for the first human trial of a benzothiazole amyloid-imaging agent [ xref ]."
"By constructing a series of chimeric mouse (Mo)/SHaPrP genes, we developed an epitopically tagged functional variant of the MoPrP gene, which can efficiently form protease-resistant PrP molecules upon expression in ScN2a cells."
"Mutations in SCN2A are thought to cause epileptic seizures by allowing an excess of sodium to enter affected neurons, causing the neurons to aberrantly fire action potentials."
"A similar phenomenon has been observed in benign familial neonatal-infantile seizures caused by mutations in the SCN2A gene, encoding the sodium channel Nav1.2, which is expressed transiently during development, thus explaining the spontaneous seizure remission with aging (Liao et al., 2010)."
"Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential."
"SCN2A level restoration was also investigated with a Cu-Zn SOD supplement using an expression study and evaluated the changes in sodium ion levels following SCN2A knockdown."
"By transfecting SH-SY5Y cells, the expression of SCN2A and the concentration of Cu-Zn SOD was analyzed and the single-cell patch clamp technique was employed in order to investigate the changes in sodium ion levels following SCN2A knockdown."
"Lower levels of SCN1A, SCN2A, SCN3A, SCN4A and SCN8A expression have also been reported in heart and shown to contribute approximately 23% of the total functional sodium channels in mouse ventricular myocytes and 27% in human atrial myocytes, based on TTX sensitivity."
"In contrast, SCN2A (sodium channel protein type 2 subunit alpha), a transmembrane sodium ion transporter, interacts with the common metabolites ATP, sodium and water, and DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase 1A), a phosphotransferase, also interacts with ATP and ADP."
"For example, Sanders et al. demonstrate in a study which identifies de novo coding mutations in 928 individuals that finding two independent de novo mutations in a single gene is highly unlikely by chance, and this occurring is viewed as evidence for association between ASD and the gene SCN2A (sodium channel, voltage gated, type II, alpha subunit) [XREF_BIBR]."
"Interaction analysis of the hcASD genes with the pASD genes revealed abundant interactions between ANK2 , SCN2A , and POGZ and the pASD genes (Fig. xref )."
"We discuss the association of SCN2A, SCN3A, GRB14, COBLL1 and SCL38A11 deletions with ASD and Tourette syndrome and possible implications for treatment."
"Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU, SMARCA4) known to cause ASD or other neurodevelopmental disorders."
"Contrary to SCN1A loss-of-function mutations in patients with severe epilepsies such as Dravet syndrome XREF_BIBR, XREF_BIBR, SCN2A gain-of-function (increased or accelerated, but not toxic) has recently been recognized as a cause of early infantile-onset severe epileptic encephalopathies such as Ohtahara syndrome, whereas loss-of-function SCN2A mutations underlie ASD or intellectual disability with later-onset mild epilepsy or without epilepsy XREF_BIBR, XREF_BIBR, XREF_BIBR."
"Mutations of the SCN2A gene encoding a voltage-gated sodium channel alpha-II subunit Nav1.2 are associated with neurological disorders such as epilepsy, autism spectrum disorders, intellectual disability, and schizophrenia."
"Contrary to the previous proposal that loss-of-function Scn2a mutations may reduce excitability of Nav1.2 expressing inhibitory neurons and thereby lead to epileptic seizures 33, we show here that the epileptic phenotypes in mice with Scn2a deficiency depend on Nav1.2 deficiency in excitatory neurons, suggesting critical contributions of impaired functions of excita-tory neurons to the pathophysiology of epileptic seizures associated with SCN2A mutations."
"A similar phenomenon has been observed in benign familial neonatal-infantile seizures caused by mutations in the SCN2A gene, encoding the sodium channel Nav1.2, which is expressed transiently during development, thus explaining the spontaneous seizure remission with aging (Liao et al., 2010)."
"For example, Sanders et al. demonstrate in a study which identifies de novo coding mutations in 928 individuals that finding two independent de novo mutations in a single gene is highly unlikely by chance, and this occurring is viewed as evidence for association between ASD and the gene SCN2A (sodium channel, voltage gated, type II, alpha subunit) [XREF_BIBR]."
"Interaction analysis of the hcASD genes with the pASD genes revealed abundant interactions between ANK2 , SCN2A , and POGZ and the pASD genes (Fig. xref )."
"We discuss the association of SCN2A, SCN3A, GRB14, COBLL1 and SCL38A11 deletions with ASD and Tourette syndrome and possible implications for treatment."
"To determine the ASO 771 concentration at which PrP C and PrP Sc levels were suppressed by 50% (half maximal effective concentration (EC 50)) in N2a and ScN2a cells, we treated cells with ASO 771 at concentrations ranging from 2 to 250nmol/l, collected lysates after 7 days, then measured PrP C and PrP Sc levels by western blot."
"Based on evidence of IL1RN haplotype containing RN2 in a group of Japanese patients with FIRES and an association of IL1RN rs4251981 G>A and SCN2A rs1864885 A>G, xref we tested for but we did not find these polymorphisms in the two genes in our patient."
"We conducted a candidate gene analysis of FIRES, focusing on the polymorphism of cytokine-related and sodium channel genes, and found a significant association of a VNTR polymorphism of the IL1RN gene and a possible association of SNPs of the IL1RN and SCN2A genes."
"We demonstrated the association of IL1RN haplotype containing RN2 with FIRES, and showed a possible association of IL1RN rs4251981 G>A and SCN2A rs1864885 A>G, in Japanese patients."
"While hyperkinetic movements are not characteristic of SCN1A -linked DS, similar movement disorders are associated with SCN2A - and SCN8A -linked EIEEs; this overlap in
symptomology led Sadleir et al to speculate that the early infantile SCN1A encephalopathy, like SCN2A - and SCN8A -linked EIEEs, may be associated with a gain-of-function
(GOF) variant—a theory that was addressed by Berecki et al in their 2019 Annals of Neurology manuscript."
"Mutations in SCN1A— and to a lesser extent SCN2A , SCN3A , and SCN9A— are associated with a variety of monogenic childhood epilepsies such as DS in humans xref – xref ."
"SCN2A mutations cause benign familial neonatal-infantile seizures (BFNIS; MIM 607745) and some cases of DS, and a mutation in SCN1B has also been identified in a patient with DS."
"We show here that CoREST, a newly identified human protein, functions as a corepressor for REST. A single zinc finger motif in REST is required for CoREST interaction. Together, REST and CoREST mediate repression of the type II sodium channel promoter in nonneural cells, and the REST/CoREST complex may mediate long-term repression essential to maintenance of cell identity."
"Therefore, REST dependent suppression of Scn2a expression may already be removed, preventing any further upregulation by overexpression of Sin3B 293."
"In the most well understood case, direct interactions between CoREST1 and REST support recruitment of LSD1/CoREST1/HDAC to multiple REST target genes such as SYN1 ( xref ; xref ) and SCN2A2 ( xref ; xref ; xref ; xref ), both of which contain REST binding sites in their promoters."
"Based on evidence of IL1RN haplotype containing RN2 in a group of Japanese patients with FIRES and an association of IL1RN rs4251981 G>A and SCN2A rs1864885 A>G, xref we tested for but we did not find these polymorphisms in the two genes in our patient."
"We conducted a candidate gene analysis of FIRES, focusing on the polymorphism of cytokine-related and sodium channel genes, and found a significant association of a VNTR polymorphism of the IL1RN gene and a possible association of SNPs of the IL1RN and SCN2A genes."
"We demonstrated the association of IL1RN haplotype containing RN2 with FIRES, and showed a possible association of IL1RN rs4251981 G>A and SCN2A rs1864885 A>G, in Japanese patients."
"The TTX sensitive alpha subunits are inhibited by TTX in the nanomolar range and include SCN1A (also known as Na v 1.1), SCN2A (also known as Na v 1.2), SCN3A (also known as Na v 1.3), SCN4A (also known as Na v 1.4), SCN8A (also known as Na v 1.6), and SCN9A (also known as Na v 1.7)."
"It is known that SCN1A (Smith et al., 1998), SCN2A (Noda et al., 1986; Suzuki et al., 1988; Smith et al., 1998), SCN3A (Suzuki et al., 1988), and SCN8A (Smith et al., 1998) alpha subunits bind tetrodotoxin and STX with comparable affinities."
"The same results were obtained when ScN2a cells were treated with U18666A, which is frequently used to induce a Niemann-Pick type C disease phenotype in cultured cells, characterized by accumulation of cholesterol in late endosomes and lysosomes [XREF_BIBR]."
"TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels."
"TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels."
"For example, mutations in SCN1A have been reported to cause epilepsy with the symptoms ranging from febrile seizures and GEFS+ to SMEI, and mutations in SCN2A are identified to cause BFNIS, GEFS+, SMEI, and intractable epilepsy with mental decline [XREF_BIBR - XREF_BIBR]."
"In addition, mutations in SCN1B, SCN2A, and GABRG2 also cause SMEI, and recently, a Dravet like phenotype in which PCDH19 and CHD2 genes are involved was described XREF_BIBR."
"By constructing a series of chimeric mouse (Mo)/SHaPrP genes, we developed an epitopically tagged functional variant of the MoPrP gene, which can efficiently form protease-resistant PrP molecules upon expression in ScN2a cells."
"Interaction analysis of the hcASD genes with the pASD genes revealed abundant interactions between ANK2 , SCN2A , and POGZ and the pASD genes (Fig. xref )."
"Transfection of ScN2a cells with a Notch-1 small interfering RNA decreased Notch-1 mRNA levels, diminished NICD concentrations, and rescued the long process phenotype."
"These results suggest that PrPSc in neurons and in ScN2a cells activates Notch-1 cleavage, resulting in atrophy of dendrites in the CNS and shrinkage of processes on the surface of cultured cells."
"Overall, our results substantially clarify the genomic architecture of ASD, demonstrate significant association of three genes SCN2A, KATNAL2 and CHD8 , and indicate that approximately 25-50 additional ASD-risk genes will be identified as sequencing of the 2,648 SSC families is completed ( xref )."
"Therefore, the present study provided a novel insight in to Cu-Zn SOD and its regulation by SCN2A in epilepsy; the decrease in SCN2A expression may reduce the concentration of Cu-Zn SOD in the brain cortex, which contributes to serious trauma to the cortex."
"Interaction analysis of the hcASD genes with the pASD genes revealed abundant interactions between ANK2 , SCN2A , and POGZ and the pASD genes (Fig. xref )."
"Interaction analysis of the hcASD genes with the pASD genes revealed abundant interactions between ANK2 , SCN2A , and POGZ and the pASD genes (Fig. xref )."
"The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2)."
"The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2)."
"Mutations of the SCN2A gene encoding a voltage-gated sodium channel alpha-II subunit Nav1.2 are associated with neurological disorders such as epilepsy, autism spectrum disorders, intellectual disability, and schizophrenia."
"Overall, our results substantially clarify the genomic architecture of ASD, demonstrate significant association of three genes SCN2A, KATNAL2 and CHD8 , and indicate that approximately 25-50 additional ASD-risk genes will be identified as sequencing of the 2,648 SSC families is completed ( xref )."
"Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels."
"Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels."
"Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels."
"Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels."
"Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels."
"Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels."
"Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels."
"Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels."
"Even the 6-hydroxy BTA-1 derivative (also called PIB or 6-OH-BTA-1) inhibited PrPSc formation in ScN2a cells with an IC 50 in the nanomolar range; more importantly, it has been selected for the first human trial of a benzothiazole amyloid-imaging agent [ xref ]."
"While hyperkinetic movements are not characteristic of SCN1A -linked DS, similar movement disorders are associated with SCN2A - and SCN8A -linked EIEEs; this overlap in
symptomology led Sadleir et al to speculate that the early infantile SCN1A encephalopathy, like SCN2A - and SCN8A -linked EIEEs, may be associated with a gain-of-function
(GOF) variant—a theory that was addressed by Berecki et al in their 2019 Annals of Neurology manuscript."
"Mutations in SCN1A— and to a lesser extent SCN2A , SCN3A , and SCN9A— are associated with a variety of monogenic childhood epilepsies such as DS in humans xref – xref ."
"Interaction analysis of the hcASD genes with the pASD genes revealed abundant interactions between ANK2 , SCN2A , and POGZ and the pASD genes (Fig. xref )."
"In contrast, SCN2A (sodium channel protein type 2 subunit alpha), a transmembrane sodium ion transporter, interacts with the common metabolites ATP, sodium and water, and DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase 1A), a phosphotransferase, also interacts with ATP and ADP."
"The inhibitor of sulfation, sodium chlorate, vastly reduces PrPSc in ScN2a cells (Gabizon, R., Meiner, Z., Halimi, M., and Ben-Sasson, S. A. (1993) J. Cell."
"Interestingly, both gain- and loss-of-function mutations of the Scn2a gene encoding the Na V 1.2 α subunit can be associated with some forms of epilepsy xref – xref ."
"When stably expressed in Chinese Hamster Lung (CHL) fibroblasts, rat beta1 and beta1A differentially modulate the function of the rat sodium channel alpha subunit Na v 1.2 (scn2a) [XREF_BIBR]."
"Upon entry into the chloroplast the Nac2 protein specifically interacts with the psbD 5'UTR and is required for the proper processing/translation of the psbD mRNA."
"Such a sequence requirement for enhanced interaction shown in our current data was previously examined by monitoring the dominant-negative inhibition of prion formation in an ScN2a cell culture system."
"Stable 22L scrapie infection was established in N2a cells (will be referred to as ScN2a cells), then PrP Sc was purified from ScN2a cells and treated with neuraminidase from Arthrobacter ureafaciens."
"Further increases in PrPres accumulation were observed in ScN2a cells treated with retinoic acid, a compound that is associated with neuronal differentiation."
"However, the activities of IRP1 and IRP2, and protein levels of TfR1 and ferritin, were still significantly lower in iron depleted ScN2a cells as compared to the N2a cells, suggesting lower need for iron in ScN2a cells."
"[26] reported that the selective, membrane-permeable cysteine protease inhibitor (2 S,3 S) - trans -epoxysuccinyl - l -leucylamido-3-methylbutane ethyl ester (E-64d) inhibited PrP Sc accumulation in ScN2a cells with an ic 50 of 0.5 muM."
"Copper acts as a key modulator of this process since its absence from PrP C side promote prion conversion, as observed in WT ScN2a cells treated with a copper chelator."
"Uninfected N2a and ScN2a cells were treated with ferric ammonium citrate (FAC) for 1-16 h, and the levels of labile iron pool (LIP), the formation of reactive oxygen species (ROS), cell viability and ferritin protein levels were measured."
"This indicates that although rab 9 overexpression reduces PrP Sc in ScN2a cells, it can attenuate the reduction of PrP Sc content in ScN2a cells induced by cholesterol accumulation in the late endocytic pathway."
"When stably expressed in Chinese Hamster Lung (CHL) fibroblasts, rat beta1 and beta1A differentially modulate the function of the rat sodium channel alpha subunit Na v 1.2 (scn2a) [XREF_BIBR]."
"Previous reports have shown that binding of anti-PrP antibodies to helix 1 region of PrP C, which is believed to play a crucial role in the conversion process XREF_BIBR, XREF_BIBR inhibits PrP Sc accumulation in ScN2a cells by preventing interaction of PrP C with PrP Sc XREF_BIBR, XREF_BIBR."
"In a different study, ScN2a neuronal cells treated with trehalose (100mM, 48h) and BafA1 (200nM, 4h) showed similar results that the LC3-II levels were increased more with treating both reagents together than with treating each alone 78."
"It is known that SCN1A (Smith et al., 1998), SCN2A (Noda et al., 1986; Suzuki et al., 1988; Smith et al., 1998), SCN3A (Suzuki et al., 1988), and SCN8A (Smith et al., 1998) alpha subunits bind tetrodotoxin and STX with comparable affinities."
"It is known that SCN1A (Smith et al., 1998), SCN2A (Noda et al., 1986; Suzuki et al., 1988; Smith et al., 1998), SCN3A (Suzuki et al., 1988), and SCN8A (Smith et al., 1998) alpha subunits bind tetrodotoxin and STX with comparable affinities."
"Interestingly, both gain- and loss-of-function mutations of the Scn2a gene encoding the Na V 1.2 α subunit can be associated with some forms of epilepsy xref – xref ."
"Upon entry into the chloroplast the Nac2 protein specifically interacts with the psbD 5'UTR and is required for the proper processing/translation of the psbD mRNA."
"Similarly, the amounts of PGE 2 produced by ScN2a cells were significantly higher than that of N2a cells (253 +/- 40 versus 118 +/- 13, n = 6, P = 0.0003)."
"Such a sequence requirement for enhanced interaction shown in our current data was previously examined by monitoring the dominant-negative inhibition of prion formation in an ScN2a cell culture system."
"As revealed in the integrated network (XREF_FIG), ASPN was the target of miRNA-374b and miRNA-21, and COL12A1 was the target of miRNA-30e, miRNA-21, and miRNA-195, while SCN2A was the target of miRNA-30e, miRNA-374b, and miRNA-195."
"ASPN was predicted as target of miR-21 and miR-374b, and COL12A1 was the target of miR-30e, miR-21, and miR-195, while SCN2A was the target of miR-30e, miR-374b, and miR-195."
"Classifying all calls produced into the ten main typical categories identified in C57BL/6J mice showed that Scn2a KO/+ pups produce a repertoire of vocalizations highly similar to their WT littermates (Additional file2 : Figure S8G-H) [XREF_BIBR, XREF_BIBR]."
"Moreover, when SENP3 was overexpressed, there was an increase in both AcH3 and diMeH3K4 levels on the SCN1A and SCN3A, but not the SCN2A2, promoters (XREF_FIG)."
"It is known that SCN1A (Smith et al., 1998), SCN2A (Noda et al., 1986; Suzuki et al., 1988; Smith et al., 1998), SCN3A (Suzuki et al., 1988), and SCN8A (Smith et al., 1998) alpha subunits bind tetrodotoxin and STX with comparable affinities."
"Scrapie infected mouse neuroblastoma (ScN2a) and hamster brain (ScHaB) cells synthesize PrPSc from the normal PrP isoform (PrPC) or a precursor through a posttranslational process."
"The absence of LPS induced NO production in ScN2a was due not to abolished enzymatic activity of iNOS but to a complete inhibition of the LPS induced iNOS gene expression as measured by Western blot and RT-PCR."
"Subsequently, it was demonstrated by ChIP and a yeast one-hybrid (Y1H) assay that EIN3 not only binds to the miR164 promoter but also directly binds to the promoters of NAC2 and another NAC-domain gene, NAP , both of which were identified as SAGs ( xref )."
"SCN2A mutations cause benign familial neonatal-infantile seizures (BFNIS; MIM 607745) and some cases of DS, and a mutation in SCN1B has also been identified in a patient with DS."
"The de novo SCN2A splice site mutation produced a stop codon 10 amino acids downstream, possibly resulting in a truncated protein and/or a nonsense mediated mRNA decay."
"Our study on the functional consequences of SCN2A variants causing the distinct phenotypes of EE, BFNIE and ID contributes to the elucidation of mechanisms underlying the broad phenotypic variability reported for SCN2A variants."
"Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels."
"Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels."
"Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels."
"Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels."
"It also reduced the seizure frequency in our patient, who had a poor response to Na + channel blockers.In conclusion, our report extends the clinical spectrum of patients with SCN2A mutations and highlights that de novo SCN2A mutations are an important cause of EOEE with movement disorders."
"Our study on the functional consequences of SCN2A variants causing the distinct phenotypes of EE, BFNIE and ID contributes to the elucidation of mechanisms underlying the broad phenotypic variability reported for SCN2A variants."
"The metabolites associated with SCN2A and DYRK1A would be less likely to be identified as differentially abundant, as ATP and ADP are used in multiple metabolic pathways and are under strong homeostatic control."
"For example, mutations in SCN1A have been reported to cause epilepsy with the symptoms ranging from febrile seizures and GEFS+ to SMEI, and mutations in SCN2A are identified to cause BFNIS, GEFS+, SMEI, and intractable epilepsy with mental decline [XREF_BIBR - XREF_BIBR]."
"Our study on the functional consequences of SCN2A variants causing the distinct phenotypes of EE, BFNIE and ID contributes to the elucidation of mechanisms underlying the broad phenotypic variability reported for SCN2A variants."
"The BFIC1 (MIM601764), BFIC2 (MIM605751) and BFIC4 (MIM612627) loci have been mapped to chromosome 19q, 16p and 1p, respectively, while BFIC3 (MIM607745) is caused by mutations in SCN2A on chromosome 2q24."
"The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons."
"Moreover, when SENP3 was overexpressed, there was an increase in both AcH3 and diMeH3K4 levels on the SCN1A and SCN3A, but not the SCN2A2, promoters (XREF_FIG)."
"While there are no obvious mutation hotspots, de novo SCN2A mutations are generally associated with more severe phenotypes than the autosomal dominant ones ( xref )."
"In contrast, SCN2A (sodium channel protein type 2 subunit alpha), a transmembrane sodium ion transporter, interacts with the common metabolites ATP, sodium and water, and DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase 1A), a phosphotransferase, also interacts with ATP and ADP."
"Mutations in the neuronal voltage-gatedsodium channel genes SCN1A and SCN2A are associated with inherited epilepsies, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (severe myoclonic epilepsy of infancy)."
"In the most well understood case, direct interactions between CoREST1 and REST support recruitment of LSD1/CoREST1/HDAC to multiple REST target genes such as SYN1 ( xref ; xref ) and SCN2A2 ( xref ; xref ; xref ; xref ), both of which contain REST binding sites in their promoters."
"We show here that CoREST, a newly identified human protein, functions as a corepressor for REST. A single zinc finger motif in REST is required for CoREST interaction. Together, REST and CoREST mediate repression of the type II sodium channel promoter in nonneural cells, and the REST/CoREST complex may mediate long-term repression essential to maintenance of cell identity."
"We further revealed that the RX mutation did not produce a truncated Nav1.2-RX peptide, but rather inactivated the mutated Scn2a allele, leading to Nav1.2 haplodeficiency in Scn2aRX/+ mice and presumably in the patient."
"ScN2a cells were also treated with 25 microg PrioV3 or ICSM35 over a period of 4 days (XREF_FIG) with daily treatment renewal in tissue culture medium."
"By constructing a series of chimeric mouse (Mo)/SHaPrP genes, we developed an epitopically tagged functional variant of the MoPrP gene, which can efficiently form protease-resistant PrP molecules upon expression in ScN2a cells."
"Subsequently, it was demonstrated by ChIP and a yeast one-hybrid (Y1H) assay that EIN3 not only binds to the miR164 promoter but also directly binds to the promoters of NAC2 and another NAC-domain gene, NAP , both of which were identified as SAGs ( xref )."
"Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α."
"[26] reported that the selective, membrane-permeable cysteine protease inhibitor (2 S,3 S) - trans -epoxysuccinyl - l -leucylamido-3-methylbutane ethyl ester (E-64d) inhibited PrP Sc accumulation in ScN2a cells with an ic 50 of 0.5 muM."
"The metabolites associated with SCN2A and DYRK1A would be less likely to be identified as differentially abundant, as ATP and ADP are used in multiple metabolic pathways and are under strong homeostatic control."
"Mutations in SCN1A— and to a lesser extent SCN2A , SCN3A , and SCN9A— are associated with a variety of monogenic childhood epilepsies such as DS in humans xref – xref ."
"Overall, our results substantially clarify the genomic architecture of ASD, demonstrate significant association of three genes SCN2A, KATNAL2 and CHD8 , and indicate that approximately 25-50 additional ASD-risk genes will be identified as sequencing of the 2,648 SSC families is completed ( xref )."
"Calpain inhibition also prevents the accumulation of PrP (Sc) in SMB and persistently infected ScN2A cells, whereas bioassay of inhibitor treated cell cultures demonstrates that calpain inhibition results in reduced prion titers compared with control treated cultures assessed in parallel."
"While there are no obvious mutation hotspots, de novo SCN2A mutations are generally associated with more severe phenotypes than the autosomal dominant ones ( xref )."
"In contrast, SCN2A (sodium channel protein type 2 subunit alpha), a transmembrane sodium ion transporter, interacts with the common metabolites ATP, sodium and water, and DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase 1A), a phosphotransferase, also interacts with ATP and ADP."
"We discuss the association of SCN2A, SCN3A, GRB14, COBLL1 and SCL38A11 deletions with ASD and Tourette syndrome and possible implications for treatment."
"Interaction analysis of the hcASD genes with the pASD genes revealed abundant interactions between ANK2 , SCN2A , and POGZ and the pASD genes (Fig. xref )."
"This study found three SNPs and one interaction among ABAT, SCN2A and ALDH5A1 were significantly associated with VPA response, which indicated that these genes may play important roles in the pharmacological mechanism of VPA."