References of "Seutin, Vincent"
     in
Bookmark and Share    
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: 59 (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: 122 (57 ULg)
Full Text
See detailCombined experimental and computational approaches to study the action of blockers of small conductance calcium-activated potassium (SK) channels
Dilly, Sébastien ULg; Lamy, Cédric; Liégeois, Jean-François ULg et al

in Acta Physiologica Scandinavica (2010), 199(supplement 678), -10

Small conductance calcium-activated potassium channels (SK) are widely expressed throughout the central nervous system (CNS) and underlie medium duration afterhyperpolarizations in many types of neurons ... [more ▼]

Small conductance calcium-activated potassium channels (SK) are widely expressed throughout the central nervous system (CNS) and underlie medium duration afterhyperpolarizations in many types of neurons. Three subtypes of SK channels, SK1, SK2 and SK3, have been identified so far in different parts of the brain. Blocking SK channels might be beneficial in the treatment of several CNS disorders such as depression, Parkinson’s disease and cognitive disorders. Until now, the precise site of interaction between these channels and their blockers has not yet been elucidated. In this context, molecular modeling is a theoretical approach that can quickly provide ideas on the binding mode of SK blockers. We first performed homology modeling of the S5-H5-S6 portion of the channels on the basis of the crystal structure of the KcsA potassium channel (Zhou et al. Nature. 2001, 414, 43-48). The binding sites of N-methyl-laudanosine (NML) (Scuvée-Moreau et al. J. Pharmacol. Exp. Ther. 2002, 302, 1176-83), a non-selective and non-peptidic ligand, and apamin (Blatz et al. Nature. 1986, 323, 718-20), an octadecapeptide with a preference for the SK2 subtype, were subsequently explored by docking analysis. Different amino-acids were suggested to interact with the two blockers. The docking of NML revealed a binding site in the turret region, far from the pore. The docking of apamin identified a very large binding site that includes a portion of the site of NML. In order to confirm the predicted binding sites, site-directed mutagenesis was used. The first mutant channels tested in electrophysiological experiments by the patch clamp technique validated some of the theoretical data. Using this strategy, we hope to get a better understanding of the mechanism of action of SK blockers and eventually find strategies to obtain subtype-selective blockers. [less ▲]

Detailed reference viewed: 30 (3 ULg)
See detailRegards croisés sur le cannabis
Seutin, Vincent ULg; Scuvée-Moreau, Jacqueline ULg; Quertemont, Etienne ULg

Book published by Mardaga (2010)

Multidisciplinary book which presents an up to date review of scientific data available on cannabis (neurobiology, toxicology, epidemiology, public health and treatment options

Detailed reference viewed: 196 (91 ULg)
Full Text
Peer Reviewed
See detailInhibition of KCa 2.2 and KCa 2.3 channel currents by protonation of outer pore histidine residues
Goodchild, Samuel; Lamy, Cédric ULg; Seutin, Vincent ULg et al

in Journal of General Physiology (2009), 134(4), 295-308

Detailed reference viewed: 69 (12 ULg)
Full Text
See detailDirect block of SK2 and SK3 current by the sigma agonist 1,3-di-(2-tolyl)guanidine
Lamy, Cédric; Moreau, Jacqueline ULg; Dilly, Sébastien ULg et al

Poster (2008, November 17)

Sigma receptors are widely distributed in the central nervous system where they modulate neurotransmitter release, receptor function, ionic channel activity and calcium homeostasis. Two subtypes of sigma ... [more ▼]

Sigma receptors are widely distributed in the central nervous system where they modulate neurotransmitter release, receptor function, ionic channel activity and calcium homeostasis. Two subtypes of sigma receptors have been identified (sigma-1 and sigma-2) with different pharmacological profiles, anatomical distribution and physiological functions. 1,3-Di-(2-tolyl)guanidine (DTG) is a sigma-1 and sigma-2 agonist which is widely used to probe the function of these receptors. It has recently been shown that sigma-1 receptor activation reduces the opening of SK channels in the hippocampus. We have observed that DTG (100 µM) reduces the apamin-sensitive afterhyperpolarization (AHP) of dopaminergic neurons within a slice preparation by ~60%, an effect not observed with other sigma agonists. In addition, neither the selective sigma-1 antagonist BD 1047 (30 µM) nor haloperidol (1 µM) blocked the effect of DTG, which suggested that the inhibition of the AHP might result from a direct block of the underlying SK channels. Whole-cell recordings were made from HEK293 cells transiently transfected with rSK2 or hSK3 cDNA in symmetrical K+ conditions with currents activated by a [Cai] of 1 µM. Expressed SK2 and SK3 channels displayed a classical pharmacology, being blocked by apamin with mean IC50’s of 100 pM and 4 nM, respectively. In contrast, both channel subtypes were blocked with equal sensitivity by N-methyl-laudanosine (NML). DTG inhibited both SK2 and SK3 currents with the same potency (IC50’s were ~30 µM). A mutation that rendered both SK2 and SK3 insensitive to apamin and NML produced a current that was still sensitive to DTG. This direct block of SK channels may be important to consider in relation to the pharmacological effects of this compound. [less ▲]

Detailed reference viewed: 30 (4 ULg)
Full Text
Peer Reviewed
See detailSK Channel blockade promotes burst firing in dorsal raphe serotonergic neurons
Rouchet, Nathalie; Waroux, Olivier ULg; Lamy, Cédric et al

in European Journal of Neuroscience (2008), 28(6), 1108-15

Detailed reference viewed: 8 (3 ULg)
Full Text
Peer Reviewed
See detailSK Channel blockade promotes burst firing in dorsal raphe serotonergic neurons
Rouchet, Nathalie ULg; Waroux, Olivier ULg; Lamy, Cédric ULg et al

in European Journal of Neuroscience (2008), 28(6), 1108-15

Detailed reference viewed: 62 (33 ULg)
Full Text
See detailMolecular modelling study of bis-isoquinolinium derivatives as small conductance Ca2+ - activated K+ channel blockers
Dilly, Sébastien ULg; Graulich, Amaury; Chavatte, Philippe et al

Poster (2008, May 30)

Small conductance calcium-activated potassium channels (SK) are widely expressed throughout the central nervous system and the periphery. Three subtypes of SK channels have been identified so far in ... [more ▼]

Small conductance calcium-activated potassium channels (SK) are widely expressed throughout the central nervous system and the periphery. Three subtypes of SK channels have been identified so far in different parts of the brain. Activation of SK channels by a rise in intracellular calcium leads to the hyperpolarisation of the membrane, hence reducing cell excitability. Blocking the SK channels might be beneficial for the treatment of depression, Parkinson’s disease and cognitive disorders. In this context, starting from the scaffold of N-methyl-laudanosine (NML) which is a known SK channel blocker (Scuvée-Moreau et al., 2002), a series of original bis-isoquinolinium derivatives were synthezised and evaluated for their affinity on the apamin-sensitive sites (Graulich et al., 2007). These quaternary compounds are powerful blockers, and the most active ones have 10 times more affinity for SK channels than dequalinium. Based on a conformational analysis, a molecular modeling study was also performed. The heads of the various conformational families were compared to a pharmacophoric model previously described (Dilly et al., 2005). The in silico results are well correlated by the in vitro binding studies. Firstly, a 6,7-dimethoxy or a 6,7,8-trimethoxy substitution is shown to be favourable. Secondly, although the length of the linker has no significant influence in the alkane derivatives, the ortho and meta linkers lead to more favourable conformations than the para linker in the xylene derivatives. [less ▲]

Detailed reference viewed: 12 (1 ULg)
Full Text
Peer Reviewed
See detailSK Channel blockade promotes bursting in vivo in dorsal raphe serotonergic neurons
Rouchet, Nathalie; Waroux, Olivier ULg; Alix, Philippe ULg et al

in Acta Physiologica (2008, May 17), 194(supll. 666), -01

Detailed reference viewed: 12 (1 ULg)
Full Text
Peer Reviewed
See detailLe système endocannabinoïde dans le cerveau... et ailleurs
Scheen, André ULg; Seutin, Vincent ULg; Van Gaal, L. F.

in Revue Médicale de Liège (2008), 63(5-6), 364-71

The endocannabinoid system is a complex system with endogenous ligands, synthesis and transport processes, specific receptors (CB1 and CB2) and intracellular degrading enzymes. It is widely distributed in ... [more ▼]

The endocannabinoid system is a complex system with endogenous ligands, synthesis and transport processes, specific receptors (CB1 and CB2) and intracellular degrading enzymes. It is widely distributed in the central nervous system, but also in peripheral organs. In the brain, endocannabinoids and CB1 receptors are almost ubiquitous and play a role in synaptic plasticity: they modulate, through an inhibitory retrograde action, the release of classical neurotransmitters such as amines, acetylcholine or amino acids. They may exert a neuroprotective effect, but are also involved in appetite and alcohol/drug dependence. At the periphery, they are present (and overexpressed in case of abdominal obesity) in various organs involved in energy control and metabolic regulation. Furthermore, CB2 receptors are also present in the brain, although less numerous than CB1 receptors. They could attenuate pain and also be neuroprotective. Selective agonists, antagonists and inverse agonists of CB1 and CB2 receptors are currently developed and open new interesting therapeutic perspectives. Rimonabant, a CB1 antagonist, has been recently launched for the treatment of obese or overweight patients at high cardiometabolic risk. [less ▲]

Detailed reference viewed: 182 (12 ULg)
Full Text
See detailRegulation of the activity of monoaminergic neurons by ion channels : an opportunity for new therapeutic approaches ?
Seutin, Vincent ULg

in Bulletin et Mémoires de l'Académie Royale de Médecine de Belgique (2008), 163(5), 213-22

Detailed reference viewed: 28 (14 ULg)
Full Text
Peer Reviewed
See detailThe SK channel blocker AG525E1 increases locomotor activity and in vivo dopamine release in the rat nucleus accumbens
Neny, M.; Lemmer, Y.; Graulich, A. et al

in Phillips, P. E. M.; Sandberg, S. G.; Ahn, S. (Eds.) et al Monitoring Molecules in Neuroscience - Proceedings of the 12th International Conference on In Vivo Methods (2008)

Detailed reference viewed: 43 (10 ULg)
Full Text
Peer Reviewed
See detailKv7 channels : interaction with dopaminergic and serotonergic neurotransmission in the CNS.
Hansen, H.; Waroux, Olivier; Seutin, Vincent ULg et al

in Journal of Physiology (2008), 586

Detailed reference viewed: 10 (4 ULg)
Full Text
Peer Reviewed
See detailBis-tetrahydroisoquinoline derivatives: AG525E1, a new step in the search for non-quaternary non-peptidic small conductance Ca2+-activated K+ channel blockers
Graulich, Amaury ULg; Lamy, Cédric ULg; Alleva, Livia ULg et al

in Bioorganic & Medicinal Chemistry Letters (2008), 18(11), 3440-3445

So far, small conductance Ca2+-activated K+ channel (SK) blockers mostly consist of quaternary ammonium derivatives or peptides. Due to their physicochemical properties, these blockers are not suitable to ... [more ▼]

So far, small conductance Ca2+-activated K+ channel (SK) blockers mostly consist of quaternary ammonium derivatives or peptides. Due to their physicochemical properties, these blockers are not suitable to study the physiological roles of SK channels in the central nervous system in vivo. Herein, we report the discovery of a chiral bis-tertiary amine with SK blocking properties from chemical modulation of laudanosine. AG525E1 has an affinity for SK channels (K-i = 293 nM) approximately 100-fold higher than the tertiary compound laudanosine (K-i similar to 30 mu M) and similar to the charged compound dequalinium (K-i = 221 nM). AG525E1 equipotently blocks SK1, SK2 and SK3 currents in transfected cell lines. Because of its basic and lipophilic properties, it can reach central SK targets. (c) 2008 Elsevier Ltd. All rights reserved. [less ▲]

Detailed reference viewed: 70 (22 ULg)
Full Text
See detailStrategies pharmacologiques de modulation de l'activite du systeme nerveux central.
Phan Ba, Remy ULg; Scuvée-Moreau, Jacqueline ULg; Seutin, Vincent ULg

in Revue Médicale de Liège (2008), 63(5-6), 238-44

There are multiple pharmacological targets in the central nervous system. After reviewing the synaptic physiology and the major neurotransmitter molecules, this article describes the main strategies used ... [more ▼]

There are multiple pharmacological targets in the central nervous system. After reviewing the synaptic physiology and the major neurotransmitter molecules, this article describes the main strategies used in neuropharmacology. The concept of specificity in the central nervous system is discussed, and allows a distinction between drugs according to the degree of specificity of their action. A catalogue of pharmacological targets is presented with therapeutic examples, and an emphasis on new agents having an original mechanism of action or acting on new targets. [less ▲]

Detailed reference viewed: 118 (24 ULg)