Sandrine Cestèle

• Nice Sophia Antipolis University

Apneic events are frightening but largely benign events that often occur in infants. Here, we report apparent life-threatening apneic events in an infant with the homozygous SCN1AL263V missense mutation, which causes familial hemiplegic migraine type 3 in heterozygous family members, in the absence of epilepsy. Observations consistent with the even...

The past two decades have witnessed a wide range of studies investigating genetic variants of voltage‐gated sodium (NaV) channels, which are involved in a broad spectrum of diseases, including several types of epilepsy. We have reviewed here phenotypes and pathological mechanisms of genetic epilepsies caused by variants in NaV α and β subunits, as...

Nav1.1 is an important pharmacological target as this voltage-gated sodium channel is involved in neurological and cardiac syndromes. Channel activators are actively sought to try to compensate for haploinsufficiency in several of these pathologies. Herein we used a natural source of new peptide compounds active on ion channels and screened for dru...

Objective This study was undertaken to refine the spectrum of SCN1A epileptic disorders other than Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+) and optimize antiseizure management by correlating phenotype–genotype relationship and functional consequences of SCN1A variants in a cohort of patients. Methods Sixteen pro...

This scientific commentary refers to ‘Gene variant effects across sodium channelopathies predict function and guide precision therapy’ by Brunklaus et al. (https://doi.org/10.1093/brain/awac006).

Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described i...

Spreading depolarizations (SDs) are involved in migraine, epilepsy, stroke, traumatic brain injury, and subarachnoid haemorrhage. However, the cellular origin and specific differential mechanisms are not clear yet. Increased glutamatergic activity is thought to be the key factor for generating cortical spreading depression (CSD), a pathological mec...

Voltage-gated sodium channels initiate action potentials in nerve, skeletal muscle, and other electrically excitable cells. Mutations in them cause a wide range of diseases. These channelopathy mutations affect every aspect of sodium channel function, including voltage sensing, voltage-dependent activation, ion conductance, fast and slow inactivati...

Cortical spreading depression (CSD) is a pathologic mechanism of migraine. We have identified a novel neocortex-specific mechanism of CSD initiation and a novel pathological role of GABAergic neurons. Mutations of the NaV1.1 sodium channel (the SCN1A gene), which is particularly important for GABAergic neurons' excitability, cause Familial Hemipleg...

Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.

BACKGROUND: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. METHODS: For this exome-based case-control study, we used...

The SCN1A gene encodes for the voltage-dependent Nav1.1 Na+ channel, an isoform mainly expressed in GABAergic neurons that is the target of hundreds of epileptogenic mutations. More recently, it has been shown that the SCN1A gene is also the target of mutations responsible for familial hemiplegic migraine (FHM-3), a rare autosomal dominant subtype...

Migraine and epilepsy are episodic disorders with distinct features, but they have some clinical and pathophysiological overlaps. We review here clinical overlaps between seizures and migraine attacks, activities of neuronal networks observed during seizures and migraine attacks, and molecular and cellular mechanisms of migraine identified in genet...

Channelopathies comprise various diseases caused by defects of ion channels. Modifications of their biophysical properties are common and have been widely studied. However, ion channels are heterogeneous multi-molecular complexes that are extensively modulated and undergo a maturation process comprising numerous steps of structural modifications an...

Les canaux sodiques dépendants du potentiel sont les acteurs majeurs de l’excitabilité neuronale. Leur rôle est exacerbé par la mise en évidence de mutations qui altèrent leur fonctionnement. La diversité des canaux sodiques (plusieurs isoformes) ainsi que leurs différentes localisations font qu’ils sont impliqués dans différentes pathologies neuro...

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and a leading cause of autism. FXS is due to the silencing of the Fragile X Mental Retardation Protein (FMRP), an RNA binding protein mainly involved in translational control, dendritic spine morphology and synaptic plasticity. Despite extensive studies, there is...

Epilepsie et migraine sont des pathologies neurologiques communes. La compréhension détaillée de leurs mécanismes pathologiques est essentielle pour le développement de nouveaux traitements efficaces.

Epileptogenic mutations have been identified in several ion channel genes, leading to the concept that several epilepsies can be considered channelopathies. However, increasing number of genes involved in a diversity of functional and developmental processes are being recognized through whole exome or genome sequencing, confirming that there is rem...

Rescuable folding defective NaV1.1 (SCN1A) mutants in epilepsy: properties, occurrence, and novel rescuing strategy with peptides targeted to the endoplasmic reticulum.

Mutations of the voltage gated Na+ channel NaV1.1 (SCN1A) are important causes of different genetic epilepsies and can also cause familial hemiplegic migraine (FHM-III). In previous studies, some rescuable epileptogenic folding defective mutants located in domain IV of NaV1.1 have been identified, showing partial loss of function also with maximal...

Mono-and poly-iodinated peptides form frequently during radioiodination procedures. However, the formation of a single species in its mono-iodinated form is essential for quantitative studies such as determination of tissue concentration or image quantification. Therefore, the aim of the present study was to define the optimal experimental conditio...

Significance Mutations of SCN1A , a gene encoding the Na v 1.1 Na ⁺ channel, can cause familial hemiplegic migraine (FHM-3) or epilepsy. Epileptogenic mutations induce reduction of its function, leading to decreased excitability of GABAergic neurons, but studies of FHM-3 mutations have generated confusing results. We have reported gain-of-function...

There has been increased interest in a possible association between epilepsy channelopathies and cardiac arrhythmias, such as long QT syndrome (LQTS). We report a kindred that features LQTS, idiopathic epilepsy, and increased risk of sudden death. Genetic study showed a previously unreported heterozygous point mutation (c.246T>C) in the KCNH2 gene....

Purpose: To report the identification of the T1174S SCN1A (NaV 1.1) mutation in a three-generation family with both epileptic and familial hemiplegic migraine (FHM) phenotypes and clarify the pathomechanism. Methods: The five affected individuals underwent detailed clinical analyses. Mutation analyses was performed by direct sequencing of SCN1A;...

Mutations of voltage-gated Na(+) channels are the most common known cause of genetically determined epilepsy; Na(v)1.1 (SCN1A) is the most frequent target. They can cause both mild and severe forms, also in patients harboring the same mutation. We have recently characterized in a family with extreme phenotypes the first epileptogenic folding-defect...

Familial hemiplegic migraine (FHM) is an autosomal dominant inherited subtype of severe migraine with aura. Mutations causing FHM (type 3) have been identified in SCN1A, the gene encoding neuronal voltage-gated Na(v)1.1 Na(+) channel alpha subunit, but functional studies have been done using the cardiac Na(v)1.5 isoform, and the observed effects we...

The gene of the four disulfide-bridged Centruroides suffusus suffusus toxin II was cloned into the expression vector pQE30 containing a 6His-tag and a FXa proteolytic cleavage region. This recombinant vector was transfected into Escherichia coli BL21 cells and expressed under induction with isopropyl thiogalactoside (IPTG). The level of expression...

Voltage-gated sodium, calcium, and potassium channels generate electrical signals required for action potential generation and conduction and are the molecular targets for a broad range of potent neurotoxins. These channels are built on a common structural motif containing six transmembrane segments and a pore loop. Their pores are formed by the S5...

Voltage sensing by voltage-gated sodium channels determines the electrical excitability of cells, but the molecular mechanism is unknown. beta-Scorpion toxins bind specifically to neurotoxin receptor site 4 and induce a negative shift in the voltage dependence of activation through a voltage sensor-trapping mechanism. Kinetic analysis showed that b...

Beta-scorpion toxins specifically modulate the voltage dependence of sodium channel activation by acting through a voltage-sensor trapping model. We used mutagenesis, functional analysis and the action of beta-toxin as tools to investigate the existence and role in channel activation of molecular interactions between the charged residues of the S2,...

Aah I is a 63-residue alpha-toxin isolated from the venom of the Buthidae scorpion Androctonus australis hector, which is considered to be the most dangerous species. We report here the first chemical synthesis of Aah I by the solid-phase method, using a Fmoc strategy. The synthetic toxin I (sAah I) was renatured in DMSO-Tris buffer, purified and s...

Alpha scorpion toxins bind to receptor site 3 on voltage-dependent sodium channels and inhibit their inactivation. The alpha-scorpion toxin BotIII is the most toxic protein of Buthus occitanus tunetanus. Its sequence differs only by three amino acid residues from that of AahII, the most active alpha-toxin. Due to their high affinity and selectivity...

A new depressant insect toxin Buthus occitanus tunetanus insect-toxin 6 (BotIT6) was purified by high-performance liquid chromatography from Buthus occitanus tunetanus (Bot) venom. BotIT6 is very active against Blatella germanica (LD50=10ng/100mg body mass) thus being one of the most potent anti-insect toxin so far characterised. When compared to o...

: Voltage-gated sodium channels serve as a target for many neurotoxins that bind to several distinct, allosterically interacting receptor sites. We examined the effect of membrane potentials (incited by increasing external K+ concentrations) on the binding modulation by veratridine, brevetoxin, and tetrodotoxin of the scorpion α-toxin AaH II to rec...

-Like toxins, a unique group designated among the scorpion -toxin class that inhibit sodium channel inactivation, are highly toxic to mice but do not compete for -toxin binding to receptor site 3 on rat brain sodium channels. We analysed the sequence of a new -like toxin, which was also highly active on insects, and studied its action and binding o...

Scorpion toxins shift the voltage dependence of activation of sodium channels to more negative membrane potentials, but only after a strong depolarizing prepulse to fully activate the channels. Their receptor site includes the S3-S4 loop at the extracellular end of the S4 voltage sensor in domain II of thesubunit. Here, we probe the role of gating...

β-Scorpion toxins shift the voltage dependence of activation of sodium channels to more negative membrane potentials, but only after a strong depolarizing prepulse to fully activate the channels. Their receptor site includes the S3–S4 loop at the extracellular end of the S4 voltage sensor in domain II of the α subunit. Here, we probe the role of ga...

Voltage-gated sodium channels are the molecular targets for a broad range of neurotoxins that act at six or more distinct receptor sites on the channel protein. These toxins fall into three groups. Both hydrophilic low molecular mass toxins and larger polypeptide toxins physically block the pore and prevent sodium conductance. Alkaloid toxins and r...

alpha-Like toxins, a unique group designated among the scorpion alpha-toxin class that inhibit sodium channel inactivation, are highly toxic to mice but do not compete for alpha-toxin binding to receptor site 3 on rat brain sodium channels. We analysed the sequence of a new alpha-like toxin, which was also highly active on insects, and studied its...

Toxin VII (TsVII), also known as Ts gamma, is the most potent neurotoxin in the venom of the Brazilian scorpion Tityus serrulatus. It has been purified to homogeneity using a new fast and efficient method. Chemical modification of TsVII with the tryptophan-specific reagent o-nitrophenylsulfenyl chloride yielded three modified derivatives (residues...

Atracotoxins are novel peptide toxins from the venom of Australian funnel-web spiders that slow sodium current inactivation in a similar manner to scorpion alpha-toxins. To analyse their interaction with known sodium channel neurotoxin receptor sites we determined their effect on scorpion toxin, batrachotoxin and saxitoxin binding. Nanomolar concen...

Polypeptide neurotoxins alter ion channel gating by binding to extracellular receptor sites, even though the voltage sensors are in their S4 transmembrane segments. By analysis of sodium channel chimeras, a beta-scorpion toxin is shown here to negatively shift voltage dependence of activation and enhance closed state inactivation by binding to a re...

delta-Atracotoxins are novel peptide toxins from the venom of Australian funnel-web spiders that slow sodium current inactivation in a similar manner to scorpion alpha-toxins, To analyse their interaction with known sodium channel neurotoxin receptor sites we determined their effect on scorpion toxin, batracbotoxin and saxitoxin binding, Nanomolar...

Two new toxins were purified from Leiurus quinquestriatus hebraeus (Lqh) scorpion venom, Lqh II and Lqh III. Lqh II sequence reveals only two substitutions, as compared to AaH II, the most active scorpion alpha-toxin on mammals from Androctounus australis Hector. Lqh III shares 80% sequence identity with the alpha-like toxin Bom III from Buthus occ...

Voltage-gated sodium channels serve as a target for many neurotoxins that bind to several distinct, allosterically interacting receptor sites. We examined the effect of membrane potentials (incited by increasing external K+ concentrations) on the binding modulation by veratridine, brevetoxin, and tetrodotoxin of the scorpion alpha-toxin AaH II to r...

Polypeptide neurotoxins alter ion channel gating by binding to extracellular receptor sites, even though the voltage sensors are in their S4 transmembrane segments. By analysis of sodium channel chimeras, a β-scorpion toxin is shown here to negatively shift voltage dependence of activation and enhance closed state inactivation by binding to a recep...

In the first part of this study density-separated, coal fractions of Point of Ayr coal were analysed using petrographic techniques and infrared (IR) spectroscopy. Density separations were carried out on the 38 + 20 μm size fraction using sodium polytungstate as the dense liquid medium. Petrographic analysis and FTIR analysis, using the diffuse refl...

Crystals of (Ba,Sr)CO3, Ba(SO4,CrO4), (Ba,Sr)SO4, and (Cd,Ca)CO3 solid solutions were obtained by counterdiffusion of reactants through a column of porous silica hydrogel. For each system, a set of experiments, starting with mother solutions of different concentrations, was carried out. The composition of the solids was analyzed by electron micropr...

Scorpion toxin Lqq III binds to a single class of high affinity (Kd = 72 +/- 19 pM) and low capacity (Bmax = 2.5 +/- 0.2 pmol/mg) binding sites in cockroach neuronal membranes. Its binding was inhibited by Lqh alpha IT (IC50 = 80 +/- 30 pM) and sea-anemone toxin ATX II (IC50 = 2.5 +/- 0.3 nM), suggesting that Lqq III is a specific probe for recepto...

alpha-Neurotoxins from scorpion venoms constitute the most studied group of modifiers of the voltage-sensitive sodium channels, and yet, their toxic site has not been characterized. We used an efficient bacterial expression system for modifying specific amino acid residues of the highly insecticidal alpha-neurotoxin LqhalphaIT from the scorpion Lei...

The insect-specific Bothus occitanus tunetanus IT2 toxin is distinguishable from other scorpion toxins by its amino acid sequence and effects on sodium conductance. The present study reveals that Bot IT2 possesses in cockroach neuronal membranes a single class of high affinity (Kd = 0.3 +/- 0.1 nM) and low capacity (Bmax = 2.4 +/- 0.5 pmol/mg) bind...

One contractive and two depressant toxins active on insect were purified by high-performance liquid chromatography from the venom of Buthus occitanus tunetanus (Bot). The two depressant toxins, BotIT4 and BotIT5, differ only at position 6 (Arg for Lys) and are equally toxic to insects (LD50 to Blatella germanica = 110 ng/100 mg body weight). They s...

A depressant toxin active on insects, Buthacus arenicola IT2, was isolated from the venom of the North African scorpion B. arenicola and its structural and pharmacological properties were investigated. B. arenicola IT2 is a single polypeptide of 61 amino acid residues, including 8 half-cystines but no methionine and histidine, with a molecular mass...

A new toxin, BotIT2, with a unique mode of action on the isolated giant axon of the cockroach Periplaneta americana and DUM (dorsal unpaired median) neurons, has been purified from the venom of the scorpion Buthus occitanus tunetanus. Its structural, antigenic and pharmacological properties are compared to those of three other groups of neurotoxins...

Voltage-sensitive sodium channels are responsible for the initiation of action potentials in many excitable cells. Several neurotoxins bind to distinct receptor sites on sodium channels and reveal strong allosteric interactions among them. Scorpion alpha toxins, which inhibit sodium channel inactivation by binding to receptor site 3, have been very...

Sodium channels posses receptor sites for many neurotoxins, of which several groups were shown to inhibit sodium current inactivation. Receptor sites that bind alpha- and alpha-like scorpion toxins are of particular interest since neurotoxin binding at these extracellular regions can affect the inactivation process at intramembranal segments of the...

At least six topologically separated neurotoxin receptor sites have been identified on sodium channels that reveal strong allosteric interactions among them. We have studied the allosteric modulation induced by veratridine, binding to receptor site 2, and brevetoxin PbTx-1, occupying receptor site 5, on the binding of alpha-scorpion toxins at recep...

At least six topologically separated neurotoxin receptor sites have been identified on sodium channels that reveal strong allosteric interactions among them. We have studied the allosteric modulation induced by veratridine, binding to receptor site 2, and brevetoxin PbTx-1, occupying receptor site 5, on the binding of α-scorpion toxins at receptor...

A cDNA encoding the Androctonus australis Hector insect toxin 1 (AaH IT1) was expressed in yeast leading to secretion of fully biologically active protein. Three different multicopy plasmids were constructed using PCR. Expression was directed by the strong PGK1 promoter of the yeast vector pMA 91. Plasmid pMA 91-AaH IT1 encodes AaH IT1 and its own...