References of "Seutin, Vincent"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailA Novel Phase Portrait to Understand Neuronal Excitability
Drion, Guillaume ULg; Franci, Alessio ULg; Seutin, Vincent ULg et al

Conference (2012, March)

Detailed reference viewed: 9 (0 ULg)
Full Text
Peer Reviewed
See detailMitochondrion- and endoplasmic reticulum-induced SK channel dysregulation as a potential origin of the selective neurodegeneration in Parkinson’s disease
Drion, Guillaume ULg; Sepulchre, Rodolphe ULg; Seutin, Vincent ULg

in Wellstead, Peter; Cloutier, Mathieu (Eds.) The Systems Biology of Parkinson's Disease (2012)

Mitochondrial dysfunction and metabolic issues are known to have strong implications in the pathogenesis of Parkinson’s disease (PD). But it is also known that the neuronal loss leading to PD symptoms is ... [more ▼]

Mitochondrial dysfunction and metabolic issues are known to have strong implications in the pathogenesis of Parkinson’s disease (PD). But it is also known that the neuronal loss leading to PD symptoms is selective for particular areas of the brain. In particular, the characteristic motor symptoms of PD are mainly due to abnormal neuronal activity in the basal ganglia, through the degeneration of substantia nigra pars compacta (SNc), but not ventral tegmental area (VTA), dopaminergic (DA) neurons. How a metabolic dysfunction triggers such a selective loss is considered from a range of perspectives in several contributions to this volume. The aim of this chapter is to investigate the potential role of small conductance calcium-activated potassium (SK) channels in this selective degeneration. Based on a recently proposed model and experimental data, we underline the fundamental role of SK channels in regulating the excitability of SNc DA neurons. The fact that SK channels do not play this regulating role in VTA DA neurons suggests the hypothesis that one reason for the preferential vulnerability of SNc DA neurons in Parkinson’s disease is that SK channels, which have a profound influence on their firing physiologically, are dysregulated by a dysfunction of mitochondria and/or endoplasmic reticulum. [less ▲]

Detailed reference viewed: 12 (0 ULg)
Full Text
Peer Reviewed
See detailAltered balance between excitatory and inhibitory inputs onto CA1 pyramidal neurons from SV2A-deficient but not SV2B-deficient mice.
Venkatesan, Kumar; Alix, Philippe ULg; Marquet, Alice et al

in Journal of Neuroscience Research (2012), 90(12), 2317-27

Synaptic vesicle protein 2 (SV2) is a glycoprotein that exists in three isoforms, SV2A, SV2B, and SV2C. SV2A knockout (KO) mice and SV2A/SV2B double KO (DKO) mice, but not SV2B KO animals, start to ... [more ▼]

Synaptic vesicle protein 2 (SV2) is a glycoprotein that exists in three isoforms, SV2A, SV2B, and SV2C. SV2A knockout (KO) mice and SV2A/SV2B double KO (DKO) mice, but not SV2B KO animals, start to experience severe seizures and weight loss 7 days after birth and die at about postnatal day (P)14-P23. Because excitatory and inhibitory inputs play a major role in controlling neuronal excitability in the hippocampus, we examined the effects of SV2A and/or SV2B deletions on glutamatergic and GABA(A) neurotransmission in hippocampal CA1 pyramidal neurons. Spontaneous and miniature excitatory and inhibitory postsynaptic currents (sEPSCs, mEPSCs, sIPSCs, and mIPSCs, respectively) were recorded using the whole-cell patch-clamp technique in slices from P6-P14 mice. The frequency of sEPSCs was increased in SV2A KO and SV2A/SV2B DKO mice, but their amplitude was unchanged. Such changes were not observed in SV2B KOs. On the contrary, the frequency and amplitude of sIPSCs were decreased in SV2A KO and SV2A/SV2B DKO mice but not in SV2B KO animals, as reported previously for the CA3 region. Kinetic parameters of sIPSCs and sEPSCs were unchanged. Importantly, no changes were observed in any genotype when examining mEPSCs and mIPSCs. We conclude that action potential- and Ca(2+) -dependent glutamatergic and GABAergic synaptic transmission are differentially altered in the hippocampus of SV2A-deficient mice, whereas the mechanism of exocytosis itself is not changed. The altered balance between these major excitatory and inhibitory inputs is probably a contributing factor to seizures in SV2A KO and SV2A/SV2B DKO mice. (c) 2012 Wiley Periodicals, Inc. [less ▲]

Detailed reference viewed: 27 (0 ULg)
Full Text
Peer Reviewed
See detailDifferential Effects of Cocaine on Dopamine Neuron Firing in Awake and Anesthetized Rats
Koulchitsky, Stanislav ULg; DE BACKER, Benjamin ULg; Quertemont, Etienne ULg et al

in Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology (2012), 37

Cocaine (benzoylmethylecgonine), a natural alkaloid, is a powerful psychostimulant and a highly addictive drug. Unfortunately, the relationships between its behavioral and electrophysiological effects are ... [more ▼]

Cocaine (benzoylmethylecgonine), a natural alkaloid, is a powerful psychostimulant and a highly addictive drug. Unfortunately, the relationships between its behavioral and electrophysiological effects are not clear. We investigated the effects of cocaine on the firing of midbrain dopaminergic (DA) neurons, both in anesthetized and awake rats, using pre-implanted multielectrode arrays and a recently developed telemetric recording system. In anesthetized animals, cocaine (10 mg/kg, intraperitoneally) produced a general decrease of the firing rate and bursting of DA neurons, sometimes preceded by a transient increase in both parameters, as previously reported by others. In awake rats, however, injection of cocaine led to a very different pattern of changes in firing. A decrease in firing rate and bursting was observed in only 14% of DA neurons. Most of the other DA neurons underwent increases in firing rate and bursting: these changes were correlated with locomotor activity in 52% of the neurons, but were uncorrelated in 29% of them. Drug concentration measurements indicated that the observed differences between the two conditions did not have a pharmacokinetic origin. Taken together, our results demonstrate that cocaine injection differentially affects the electrical activity of DA neurons in awake and anesthetized states. The observed increases in neuronal activity may in part reflect the cocaine-induced synaptic potentiation found ex vivo in these neurons. Our observations also show that electrophysiological recordings in awake animals can uncover drug effects, which are masked by general anesthesia. [less ▲]

Detailed reference viewed: 43 (12 ULg)
Full Text
Peer Reviewed
See detailSynthesis and radioligand binding studies of bis-(8-isopropylisoquinolinium) derivatives as ligands for apamin-sensitive sites on cloned SK2 and SK3 channels
Badarau, Eduard; Dilly, Sébastien ULg; Dufour, Fabien et al

in Bioorganic & Medicinal Chemistry Letters (2011), 21(22), 6756-6759

A structure-activity relationship study of N-methyl-laudanosine, a SK channel blocker, has indicated that the 6,7-dimethoxy group could be successfully replaced by a hydrophobic moiety such as an ... [more ▼]

A structure-activity relationship study of N-methyl-laudanosine, a SK channel blocker, has indicated that the 6,7-dimethoxy group could be successfully replaced by a hydrophobic moiety such as an isopropyl substituent in position 8 of the isoquinoline ring. In the present study, bis-(8-isopropyl-isoquinolinium) derivatives (2a-e) were synthesized and tested for their affinity for cloned SK2 and SK3 channels in comparison with their 6,7-dimethoxy analogues (4a-f). Several ligands were investigated, both in flexible (propyl, butyl and pentyl) and rigid (m- or p-xylyl) series, the m-xylyl derivative (2d) having the best profile in terms of affinity and selectivity for SK3/SK2 channels. Molecular studies showed that the optimal conformation of compound 2d fits well with our SK pharmacophore model. [less ▲]

Detailed reference viewed: 67 (12 ULg)
Full Text
Peer Reviewed
See detail11-Deoxycortisol impedes GABAergic neurotransmission and induces drug-resistant status epilepticus in mice
Kaminski, R. M.; Venkatesan, Kumar ULg; Mazzuferi, Manuela ULg et al

in Neuropharmacology (2011), 60(7-8), 1098-1108

Detailed reference viewed: 18 (1 ULg)
Full Text
Peer Reviewed
See detailIon channel modulators: more diversity than previously thought
Dilly, Sébastien ULg; Lamy, Cédric; Marrion, Neil et al

in Chembiochem : A European Journal of Chemical Biology (2011), 12(12), 1808-1812

Ion channel function can be modified in various ways. For example, numerous studies have shown that currents through voltage-gated ion channels are affected by pore block or modification of voltage ... [more ▼]

Ion channel function can be modified in various ways. For example, numerous studies have shown that currents through voltage-gated ion channels are affected by pore block or modification of voltage-dependence of activation/inactivation. Recent experiments performed on various ion channels show that allosteric modulation is an important mechanism to affect channel function. For instance, in KCa2 (formerly SK) channels, the prototypic “blocker” apamin prevents conduction by an allosteric mechanism, while TRPV1 channels are prevented from closing by a tarantula toxin, DkTx, through an interaction with residues located away from the selectivity filter. The recent evidence therefore suggests that, in several ion channels, the region around the outer mouth of the pore is rich in binding sites which may be exploited therapeutically. These discoveries also suggest that the pharmacological vocabulary should be adapted to define these various actions. [less ▲]

Detailed reference viewed: 63 (15 ULg)
Full Text
Peer Reviewed
See detailCrucial role of a shared extracellular loop in apamin sensitivity and maintenance of pore shape of small-conductance calcium-activated potassium (SK) channel
Weatherall, Kate; Seutin, Vincent ULg; Liégeois, Jean-François ULg et al

in Proceedings of the National Academy of Sciences of the United States of America (2011), 108(45), 18488-18493

Detailed reference viewed: 36 (8 ULg)
Full Text
See detailBlock of SK channels by the sigma agonist 1,3-di-o-tolyl-guanidine: evidence for a novel site of action for SK blockers
Dilly, Sébastien ULg; Lamy, Cédric; Snyders, Dirk et al

Poster (2010, October 16)

Among ion channels involved in the control of neuronal activity, small conductance calcium-activated potassium channels (SK) represent an interesting therapeutic target. Indeed, they underlie medium ... [more ▼]

Among ion channels involved in the control of neuronal activity, small conductance calcium-activated potassium channels (SK) represent an interesting therapeutic target. Indeed, they underlie medium duration afterhyperpolarizations (mAHPs) in many types of neurons, thus inhibiting cell excitability. Three subtypes of SK subunits, SK1, SK2 and SK3, have been cloned and are expressed differentially within the central nervous system (CNS). Blocking SK channels might be beneficial in the treatment of several CNS disorders such as depression (SK3), Parkinson’s disease (SK3) and cognitive disorders (SK2). So far, the prototypical blocker of SK channels is apamin, an octadecapeptide from bee venom. We have recently shown that apamin blocks SK channels by binding to a site distinct from that used by classical pore blockers such as tetraethylammonium (TEA) (Lamy et al. J. Biol. Chem. 2010, 285, 27067-77). We have also demonstrated that the nonpeptide blocker N-methyl-laudanosine (NML) (Scuvée-Moreau et al. J. Pharmacol. Exp. Ther. 2002, 302, 1176-83) competes for the binding site of the toxin. Further, our research team has recently shown that the sigma agonist 1,3-di-o-tolyl-guanidine (DTG) directly blocks SK currents in a voltage-independent manner (Lamy et al. Eur. J. Pharmacol. 2010, 641, 23-8). We have combined patch clamp experiments on cell lines with molecular modelling and mutagenesis, to try to identify the site where DTG blocks. DTG was found to be equipotent on wild-type (WT) and apamin-insensitive (e.g. SK2H337N) channels. Moreover, mutated channels with increased sensitivity to TEA (SK3V520F: mean IC50 of TEA: 0.34 mM versus 11 mM for WT channels) were blocked by DTG with the same potency as WT channels. Thus, DTG does not seem to share the site of either apamin or TEA. Modelling data were in agreement with this possibility because of the identification of various potential binding sites. Although preliminary, these results suggest the existence of yet another binding site in the outer pore region of SK channels. [less ▲]

Detailed reference viewed: 41 (12 ULg)
Full Text
See detailEtude du mode de liaison des canaux potassiques de type SK et l’apamine par modélisation moléculaire
Dilly, Sébastien ULg; Lamy, Cédric; Seutin, Vincent ULg et al

Poster (2010, May 20)

Parmi les canaux ioniques impliqués dans le contrôle de l'activité neuronale, les canaux potassiques calcium-dépendants de basse conductance, dénommés canaux SK, constituent une cible thérapeutique ... [more ▼]

Parmi les canaux ioniques impliqués dans le contrôle de l'activité neuronale, les canaux potassiques calcium-dépendants de basse conductance, dénommés canaux SK, constituent une cible thérapeutique intéressante. En effet, ils sous-tendent la posthyperpolarisation ("AfterHyperPolarization") de durée moyenne (mAHP) qui limite l'excitabilité de divers types de neurones du système nerveux central (SNC). A ce jour, 3 types de sous-unités, SK1, SK2 et SK3, ont été identifiés dans différentes régions du cerveau. Le blocage sélectif de ces canaux pourrait être bénéfique dans le traitement de divers troubles du SNC comme la maladie de Parkinson (SK3), la dépression (SK3) ou encore les désordres cognitifs (SK2) (Liégeois et al., 2003 ; Pedarzani et al., 2008). Jusqu’à présent, le site d’interaction entre les canaux SK et leurs bloqueurs n’a pas encore été précisément élucidé. Dans ce contexte, nous avons entrepris la modélisation de ces canaux par homologie comparative en se basant sur la structure cristalline du canal potassique KCSA (Doyle et al., 1998). La construction de ces canaux constitue la première étape dans la détermination des requis structuraux essentiels à l’affinité de bloqueurs et à la compréhension des modes de liaison de ces ligands. Le mode de liaison de l’apamine, bloqueur peptidique issu du venin d’abeille, a été ensuite exploré par « docking ». Afin de confirmer ce site de liaison potentiel, des expériences de mutagénèse dirigée ont été réalisées. Les premiers canaux mutants testés dans des expériences électrophysiologiques par la technique de « patch clamp » ont permis de valider certaines données théoriques. Grâce à cette stratégie, nous espérons préciser le mécanisme d'action des bloqueurs des canaux SK et, idéalement, découvrir des pistes pour concevoir des bloqueurs sélectifs. [less ▲]

Detailed reference viewed: 77 (5 ULg)
Full Text
Peer Reviewed
See detailAllosteric block of KCa2 channels by apamin
Lamy, Cédric ULg; Goodchild, Samuel J; Weatherall, Kate L et al

in Journal of Biological Chemistry (2010)

Detailed reference viewed: 57 (23 ULg)
Full Text
Peer Reviewed
See detailM-type channels selectively control bursting in rat dopaminergic neurons
Drion, Guillaume ULg; Bonjean, Maxime; Waroux, Olivier ULg et al

in European Journal of Neuroscience (2010), 31

Detailed reference viewed: 125 (59 ULg)