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See detailInteractions between calcium channels and SK channels in midbrain dopamine neurons and their impact on pacemaker regularity: Contrasting roles of N- and L-type channels.
de Vrind, V.; Scuvée-Moreau, Jacqueline ULg; Drion, Guillaume ULg et al

in European Journal of Pharmacology (2016)

Although small-conductance Ca2+-activated K+ (SK) channels and various types of voltage-gated Ca2+ (Cav) channels have been described in midbrain dopaminergic neurons, the nature of their interactions is ... [more ▼]

Although small-conductance Ca2+-activated K+ (SK) channels and various types of voltage-gated Ca2+ (Cav) channels have been described in midbrain dopaminergic neurons, the nature of their interactions is unclear. More particularly, the role of various Cav channel types in either promoting irregularity of firing (by generating an inward current during SK channel blockade) or promoting regularity of firing (by providing the source of Ca2+ for the activation of SK channels) has not been systematically explored. We addressed this question using intracellular and extracellular recordings from substantia nigra, pars compacta (SNc), dopaminergic neurons in rat midbrain slices. Neurons were pharmacologically isolated from their differences. When examining the ability of various Cav channel blockers to inhibit the SK-mediated afterhyperpolarization (AHP), we found that only the N-type Cav channel blocker ω-conotoxin-GVIA was able to reduce the apamin-sensitive AHP, but only partially (~40%). Specific blockers of L, P/Q, T or R channels had no effect on this AHP. Combining ω-conotoxin-GVIA and other specific blockers did not yield greater block and even the broad Cav blocker Cd2+ induced a submaximal (~75%) effect. Extracellular recordings examining firing regularity yielded congruent results: none of the specific blockers was able to increase firing irregularity to the extent that the specific SK blocker apamin did. The irregularity of firing observed with apamin could only be reversed by blocking L-type Ca2+ channels. Thus various sources of Ca2+ appear to be required for SK channel activation in SNc neurons (some of them still unidentified), ensuring robustness of pacemaking regularity. [less ▲]

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See detailDifferential somatic Ca2+ channel profile in midbrain dopaminergic neurons
Philippart, Fabian ULg; Destreel, Geoffrey ULg; Merino-Sepulveda, Paulina et al

in Journal of Neuroscience (2016)

Dopaminergic (DA) neurons located in the ventral midbrain continuously generate a slow endogenous pacemaker activity, the mechanism of which is still debated. It has been suggested that, in the substantia ... [more ▼]

Dopaminergic (DA) neurons located in the ventral midbrain continuously generate a slow endogenous pacemaker activity, the mechanism of which is still debated. It has been suggested that, in the substantia nigra pars compacta (SNc), the pacemaking relies more on Ca2+ channels and that the density of L type Ca2+ channels is higher in these DA neurons than in those located in the ventral tegmental area (VTA). This might lead to a higher Ca2+ load in SNc DA neurons, and explain their higher susceptibility to degeneration. However, direct evidence for this hypothesis is lacking. We found that the L-type current and channel density is indeed higher in the somata of rat SNc DA neurons, and that this current undergoes less inactivation in this region. Non stationary fluctuation analysis (NSFA) measurements showed a much higher number of L-type channels in the soma of SNc DA neurons, as well as a smaller single channel conductance, pointing to a possible different molecular identity of L-type channels in DA neurons from the two areas. A major consequence of this is that pacemaking and even more so bursting are associated with a larger Ca2+ entry through L-type channels in SN DA neurons than in their VTA counterparts. Our results establish a molecular and functional difference between two populations of midbrain DA neurons that may contribute to their differential sensitivity to neurodegeneration. [less ▲]

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See detailDopaminergic neurons differentiating from LRRK2 G2019S induced pluripotent stem cells show early neuritic branching defects.
Borgs, Laurence; Peyre, Elise ULg; Alix, Philippe et al

in Scientific Reports (2016), 6

Some mutations of the LRRK2 gene underlie autosomal dominant form of Parkinson's disease (PD). The G2019S is a common mutation that accounts for about 2% of PD cases. To understand the pathophysiology of ... [more ▼]

Some mutations of the LRRK2 gene underlie autosomal dominant form of Parkinson's disease (PD). The G2019S is a common mutation that accounts for about 2% of PD cases. To understand the pathophysiology of this mutation and its possible developmental implications, we developed an in vitro assay to model PD with human induced pluripotent stem cells (hiPSCs) reprogrammed from skin fibroblasts of PD patients suffering from the LRKK2 G2019S mutation. We differentiated the hiPSCs into neural stem cells (NSCs) and further into dopaminergic neurons. Here we show that NSCs bearing the mutation tend to differentiate less efficiently into dopaminergic neurons and that the latter exhibit significant branching defects as compared to their controls. [less ▲]

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See detailMecanismes de l'effet diuretique de la cafeine.
Marx, Barbara; Scuvee, Eleonore; Scuvée-Moreau, Jacqueline ULg et al

in Medecine sciences : M/S (2016), 32(5), 485-90

Caffeine is an alkaloid which belongs to the family of methylxanthines and is present in beverages, food and drugs. Caffeine competitively antagonizes the adenosine receptors (AR), which are G protein ... [more ▼]

Caffeine is an alkaloid which belongs to the family of methylxanthines and is present in beverages, food and drugs. Caffeine competitively antagonizes the adenosine receptors (AR), which are G protein-coupled receptors largely distributed throughout the body, including brain, heart, vessels and kidneys. Caffeine consumption has a well-known diuretic effect. The homeostasis of salt and water involves different segments of the nephron, in which adenosine plays complex roles depending on the differential expression of AR. Hence, caffeine increases glomerular filtration rate by opposing the vasoconstriction of renal afferent arteriole mediated by adenosine via type 1 AR during the tubuloglomerular feedback. Caffeine also inhibits Na(+) reabsorption at the level of renal proximal tubules. In addition, caffeine perturbs the hepatorenal reflex via sensory nerves in Mall's intrahepatic spaces. Here, we review the physiology of caffeine-induced natriuresis and diuresis, as well as the putative pathological implications. [less ▲]

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See detailCorrelation between ethanol behavioral sensitization and midbrain dopamine neuron reactivity to ethanol
Didone, Vincent ULg; Masson, Sébastien; Quoilin, Caroline et al

in Addiction Biology (2016), 21(2), 387-396

Repeated ethanol injections lead to a sensitization of its stimulant effects in mice. Some recent results argue against a role for ventral tegmental area (VTA) dopamine neurons in ethanol behavioral ... [more ▼]

Repeated ethanol injections lead to a sensitization of its stimulant effects in mice. Some recent results argue against a role for ventral tegmental area (VTA) dopamine neurons in ethanol behavioral sensitization. The aim of the present study was to test whether in vivo ethanol locomotor sensitization correlates with changes in either basal- or ethanol evoked firing rates of dopamine neurons in vitro. Female Swiss mice were daily injected with 2.5 g/kg ethanol (or saline in the control group) for 7 days and their locomotor activity was recorded. At the end of the sensitization procedure, extracellular recordings were made from dopaminergic neurons in midbrain slices from these mice. Significantly higher spontaneous basal firing rates of dopamine neurons were recorded in ethanol-sensitized mice relative to control mice, but without correlations with the behavioral effects. The superfusion of sulpiride, a dopamine D2 antagonist, induced a stronger increase of dopamine neuron firing rates in ethanol-sensitized mice. This shows that the D2 feedback in dopamine neurons is preserved after chronic ethanol administration and argues against a reduced D2 feedback as an explanation for the increased dopamine neuron basal firing rates in ethanol-sensitized mice. Finally, ethanol superfusion (10–100 mM) significantly increased the firing rates of dopamine neurons and this effect was of higher magnitude in ethanol-sensitized mice. Furthermore, there were significant correlations between such a sensitization of dopamine neuron activity and ethanol behavioral sensitization. These results support the hypothesis that changes in brain dopamine neuron activity contribute to the behavioral sensitization of the stimulant effects of ethanol. [less ▲]

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See detailHigh dendritic expression of Ih in the proximity of the axon origin controls the integrative properties of nigral dopamine neurons.
Engel, Dominique ULg; Seutin, Vincent ULg

in Journal of Physiology (2015), 593(22), 4905-4922

Dendrites of most neurons express voltage-gated ion channels in their membrane. In combination with passive properties, active currents confer to dendrites a high computational potential. The ... [more ▼]

Dendrites of most neurons express voltage-gated ion channels in their membrane. In combination with passive properties, active currents confer to dendrites a high computational potential. The hyperpolarization-activated cation current Ih present in the dendrites of some pyramidal neurons affects their membrane and integration properties, synaptic plasticity and higher functions such as memory. A gradient of increasing h-channel density towards distal dendrites has been found to be responsible for the location independence of excitatory postsynaptic potential (EPSP) waveform and temporal summation in cortical and hippocampal pyramidal cells. However, reports on other cell types revealed that smoother gradients or even linear distributions of Ih can achieve homogeneous temporal summation. Although the existence of a robust, slowly activating Ih current has been repeatedly demonstrated in nigral dopamine neurons, its subcellular distribution and precise role in synaptic integration are unknown. Using cell-attached patch-clamp recordings, we find a higher Ih current density in the axon-bearing dendrite than in the soma or in dendrites without axon in nigral dopamine neurons. Ih is mainly concentrated in the dendritic membrane area surrounding the axon origin and decreases with increasing distances from this site. Single EPSPs and temporal summation are similarly affected by blockade of Ih in axon- and non-axon-bearing dendrites. The presence of Ih close to the axon is pivotal to control the integrative functions and the output signal of dopamine neurons and may consequently influence the downstream coding of movement. [less ▲]

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See detailL'alcool en questions
Seutin, Vincent ULg; Scuvée-Moreau, Jacqueline ULg; Quertemont, Etienne ULg

Book published by Mardaga (2015)

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See detail11. Si on prend un médicament, faut-il s'abstenir de boire de l'alcool ?
Scuvée-Moreau, Jacqueline ULg; Charlier, Corinne ULg; Seutin, Vincent ULg

in Seutin, Vincent; Scuvée-Moreau, Jacqueline; Quertemont, Etienne (Eds.) L'alcool en questions (2015)

L’alcool remonte le moral. Une petite cuite n’a jamais tué personne. Boire un café atténue l’effet de l’alcool. Le binge drinking est un fléau nouveau… De nombreuses idées reçues, certaines fondées ... [more ▼]

L’alcool remonte le moral. Une petite cuite n’a jamais tué personne. Boire un café atténue l’effet de l’alcool. Le binge drinking est un fléau nouveau… De nombreuses idées reçues, certaines fondées, d’autres pas, sont véhiculées à propos de l’alcool et de ses conséquences. L’alcool soulève aussi de multiples questions : L’alcool est-il une drogue ? L’alcool est-il aphrodisiaque ? L’alcoolisme est-il héréditaire ? Combien l’alcool coûte/rapporte-t-il à la société ? Peut-on guérir de l’alcoolisme ?… Ce livre a pour but de démont(r)er certaines idées reçues sur l’alcool et d’apporter des réponses aux questions que chacun se pose. Les auteurs ne se bornent pas à répondre par vrai ou faux, ils fournissent les explications, appuyées sur l’état des connaissances scientifiques actuelles, qui permettent d’infirmer ou de confirmer ces idées reçues ou de répondre à ces questions. Ils nuancent le propos lorsque la réponse n’est pas de l’ordre du tout ou rien. Il est indéniable que l’excès d’alcool est nuisible à la santé. Il existe cependant une littérature scientifique démontrant des effets positifs sur la santé de la consommation en quantités modérées de certaines boissons alcoolisées. Ce mélange d’effets positifs et négatifs explique que le public a développé une relation d’amour-haine avec l’alcool. Ainsi, les abstinents complets sont parfois qualifiés de rabat-joie. Les alcooliques chroniques (5 à 10 % des occidentaux, selon les études épidémiologiques !) sont, quant à eux, souvent trop vite jugés. Ce qui est certain c’est que l’alcoolo-dépendance est source de beaucoup de souffrances pour la personne et son entourage. Ces 41 réponses à des questions sur l’alcool visent à donner des balises au lecteur, littérature scientifique à l’appui. [less ▲]

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See detailCalcium-dependent potassium channels.
Drion, Guillaume ULg; Philippart, Fabian ULg; Sepulchre, Rodolphe ULg et al

in Jaeger, Dieter; Jung, Ranu (Eds.) Encyclopedia of Computational Neuroscience (2015)

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See detailA PREFERENTIAL FOLDED CONFORMATION OF SOME BIS-(8-ISOPROPYL-ISOQUINOLINIUM) DERIVATIVES EXPLAINS STEREOSELECTIVE REDUCTION BY SODIUM BOROHYDRIDE
Dilly, Sébastien ULg; Badarau, Eduard; Dufour, Fabien et al

Poster (2014, June 05)

Small conductance Ca2+-activated K+ (SK) channels play a role in modulating the firing rate and the firing pattern of neurons [Waroux, Eur J Neurosci, 2005, 22, 3111]. A blockade of these targets could be ... [more ▼]

Small conductance Ca2+-activated K+ (SK) channels play a role in modulating the firing rate and the firing pattern of neurons [Waroux, Eur J Neurosci, 2005, 22, 3111]. A blockade of these targets could be useful for the treatment of cognitive dysfunction, neuronal hyperexcitability or dopamine related disorders [Liégeois, Curr Med Chem, 2003, 10, 625]. At the peripheral level, the inhibition of these channels was demonstrated to prevent and terminate atrial fibrillation [Diness, Circ Arrhythm Electrophysiol, 2010, 3, 380]. Moreover, SK channels might represent potential targets for a new class of anticancer agents due to their involvement in breast cancer cell migration [Potier, Mol Cancer Ther, 2006, 5, 2946]. So far, available blockers are not suitable CNS pharmacological tools being either peptides or small molecules with permanent positive charges [Liégeois, Curr Med Chem, 2003, 10, 625; Graulich, J Med Chem, 2007, 50, 5070; Badarau, Bioorg Med Chem Lett, 2011, 21, 6756]. Therefore, symmetrical bis-isoquinolinium compounds have subsequently been transformed to 1,2,3,4-tetrahydroisoquinoline analogues by using sodium borohydride leading to a diastereoisomeric mixture (figure 1) in order to obtain potential CNS-penetrating agents [Graulich, Bioorg Med Chem Lett, 2008, 18, 3440; Neny, Proceedings of the 12th International Conference on In Vivo Methods, Vancouver, Canada, 2008, 267; Koulchitsky, Acta Physiologica, 2009, 195, 670]. Resolution of these mixtures and characterization of the corresponding stereoisomers [Wouters, Eur J Med Chem, 2010, 45, 3240] are necessary before further biological evaluation. In a series of 8- isopropyl analogues, chiral resolution failed for the analogues with propyl and m-xylyl linkers since two and one peaks, respectively, were detected [Nistor, J Pharm Biomed Anal, 2013, 74, 273]. Could these results be explained by an ineffective resolution or would another phenomenon be involved? Further analysis using chiral chromatography, mass spectroscopy and circular dichroism of a sample of the propyl analogue revealed that it is a racemic mixture. X-ray cristallography and conformational analysis indicated a folded conformation of the propyl and m-xylyl analogues (figure 2) responsible for a stereoselective attack of the borohydride reagent during the reduction step. Additional 1H-NMR investigations support structural features detected by theoretical analysis. [less ▲]

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See detailStructural analysis of some bis-(8-isopropyl-isoquinolinium) derivatives reveals a preferential folded conformation leading to a stereoselective attack by sodium borohydride
Dilly, Sébastien ULg; Badarau, Eduard; Dufour, Fabien et al

in Journal of Molecular Structure (2014)

Reduction of symmetrical bis-isoquinolinium derivatives with sodium borohydride generates normally a mixture of three 1,2,3,4-tetrahydroisoquinoline stereoisomers. In a series of 8- isopropyl analogues ... [more ▼]

Reduction of symmetrical bis-isoquinolinium derivatives with sodium borohydride generates normally a mixture of three 1,2,3,4-tetrahydroisoquinoline stereoisomers. In a series of 8- isopropyl analogues, chiral resolution failed for the analogues with propyl and m-xylyl linkers since two and one peaks respectively were detected by HPLC. Further analysis by MS and CD of both peaks of the propyl analogue revealed that each peak corresponds to an enantiomer. Conformational analysis and X-ray cristallography showed a folded conformation of the propyl and m-xylyl analogues responsible for the observed stereoselectivity following the reduction step. Additional 1H NMR investigations confirm structural features detected by theoretical analysis. [less ▲]

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See detailChemical modifications of the N-methyl laudanosine scaffold point to new directions for SK channels exploration
Badarau, Eduard; Dilly, Sébastien ULg; Wouters, Johan et al

in Bioorganic & Medicinal Chemistry Letters (2014), 24

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See detailMechanism of the medium-duration afterhyperpolarization in rat serotonergic neurons
Alix, Philippe ULg; Venkatesan, Kumar; Scuvée-Moreau, Jacqueline et al

in European Journal of Neuroscience (2014), 39(2), 186-196

Most serotonergic neurons display a prominent medium-duration afterhyperpolarization (mAHP), which is mediated by small conductance Ca2+-activated K+ (SK) channels. Recent ex vivo and in vivo experiments ... [more ▼]

Most serotonergic neurons display a prominent medium-duration afterhyperpolarization (mAHP), which is mediated by small conductance Ca2+-activated K+ (SK) channels. Recent ex vivo and in vivo experiments have suggested that SK channel blockade increases the firing rate and/or bursting in these neurons. The purpose of this study was therefore to characterize the source of Ca2+ which activates the mAHP channels in serotonergic neurons. In voltage clamp experiments, an outward current was recorded at -60 mV after a depolarizing pulse to + 100 mV. A supra-maximal concentration of the SK channel blockers apamin or (-)- bicuculline methiodide blocked this outward current. This current was also sensitive to the broad Ca2+ channel blocker Co2+ and was partially blocked by both ω-conotoxin and mibefradil, which are blockers of N-type and T-type Ca2+ channels, respectively. Neither blockers of other voltage-gated Ca2+ channels nor DBHQ, an inhibitor of Ca2+-induced Ca2+ release, had any effect on the SK current. [less ▲]

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See detailBis-(1,2,3,4-tetrahydroisoquinolinium): a chiral scaffold for developing high affinity ligands for SK channels
Liégeois, Jean-François ULg; Wouters, Johan; Seutin, Vincent ULg et al

in ChemMedChem (2014), 9

N-Methyl-bis-(1,2,3,4-tetrahydroisoquinolinium) analogues derived from AG525 (1,1'-(propane-1,3-diyl)-bis-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline)) stereoisomers and tetrandrine, a rigid ... [more ▼]

N-Methyl-bis-(1,2,3,4-tetrahydroisoquinolinium) analogues derived from AG525 (1,1'-(propane-1,3-diyl)-bis-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline)) stereoisomers and tetrandrine, a rigid bis-(1,2,3,4-tetrahydroisoquinoline) analogue with an S,S configuration, were synthesized and tested for their affinity for small-conductance calcium-activated potassium channel (SK/KCa2) subtypes using radioligand binding assays. A significant increase in affinity was observed for the quaternized analogues over the parent 1,2,3,4-tetrahydroisoquinoline compounds. Interestingly, the impact of stereochemistry was not the same in the two groups of compounds. For quaternized analogues, affinities of S,S and R,R isomers for SK2 and SK3 channels were similar and in both cases higher than that of the meso derivative. Among the bis-tetrahydroisoquinoline compounds, the S,S isomers exhibited high affinity, while the R,R and meso isomers had similarly lower affinities. Furthermore, the SK2/SK3 selectivity ratio was slightly increased for quaternized analogues. Bis-(1,2,3,4-tetrahydroisoquinolinium) represents a new scaffold for the development of high-affinity ligands for SK channel subtypes [less ▲]

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See detailIncreased affinity of N-Methyl-AG525 stereoisomers for SK2 and SK3 channels
Liégeois, Jean-François ULg; Seutin, Vincent ULg; Dilly, Sébastien ULg

Poster (2013, November 09)

Small conductance calcium-activated potassium (SK, KCa2) channels represent interesting and challenging targets in medicinal chemistry. So far, the reference ligand is apamin, a peptide used in most ... [more ▼]

Small conductance calcium-activated potassium (SK, KCa2) channels represent interesting and challenging targets in medicinal chemistry. So far, the reference ligand is apamin, a peptide used in most published studies including the [125I] analog for binding studies. Nonpeptidic ligands with high affinity have been developed for several years. Currently, different questions remain to be solved. No selective and brain-penetrating agent is available. In addition, replacing [125I]apamin in binding experiments would be also interesting. We have developed different series of compounds initially derived from laudanosine (1). The quaternized derivative, N-methyl-laudanosine (NML), was found to be a weak SK blocker but highly reversible in electrophysiological experiments (2). Then, bis-charged derivatives were synthesized. Potentially brain-penetrating AG525 stereoisomers were obtained and tested for their affinity for SK channels (3). The affinity of one enantiomer, AG525E1, was found to be close to that of dequalinium (Ki ~ 200 nM) while the two other stereoisomers had a lower affinity. Following this study, quaternization of AG525 stereoisomers was carried out and the affinity of these compounds for SK channel subtypes was determined in comparison with that of parent compounds. We observed a significant increase of affinity for SK2 and SK3 channels for the bis-charged N-methyl derivatives as compared to the basic AG525 stereoisomers to. The ratio of selectivity was increased a little in the case of bis-charged N-methyl derivatives. In addition, the influence of stereochemistry was quite different between both groups. For basic AG525 stereoisomers, the S,S-enantiomer (AG525E1) was the most potent while, within bis-charged N-methyl analogues, both enantiomers had higher affinity. Further in silico approaches should permit to explain these results. References: (1) Graulich et al., Bioorg. Med. Chem. 2005, 13, 1201 (2) Scuvée-Moreau et al., J. Pharmacol. Exp. Ther. 2002, 302, 1176 (3) Graulich et al., Bioorg. Med. Chem. Lett., 2008, 18, 3440 [less ▲]

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See detailPrincipes du traitement pharmacologique de l'addiction
Saadan, Myriam; Scuvée, Jacqueline ULg; Seutin, Vincent ULg

in Revue Médicale de Liège (2013), 68(5-6), 245-251

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