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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 (in press)

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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 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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See detailA Balance Equation Determines a Switch in Neuronal Excitability
Franci, Alessio ULg; Drion, Guillaume ULg; Seutin, Vincent ULg et al

in PLoS Computational Biology (2013)

We use the qualitative insight of a planar neuronal phase portrait to detect an excitability switch in arbitrary conductance-based models from a simple mathematical condition. The condition expresses a ... [more ▼]

We use the qualitative insight of a planar neuronal phase portrait to detect an excitability switch in arbitrary conductance-based models from a simple mathematical condition. The condition expresses a balance between ion channels that provide a negative feedback at resting potential (restorative channels) and those that provide a positive feedback at resting potential (regenerative channels). Geometrically, the condition imposes a transcritical bifurcation that rules the switch of excitability through the variation of a single physiological parameter. Our analysis of six di erent published conductance based models always nds the transcritical bifurcation and the associated switch in excitability, which suggests that the mathematical predictions have a physiological rel- evance and that a same regulatory mechanism is potentially involved in the excitability and signaling of many neurons. [less ▲]

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See detailThe interactions of apamin and tetraethylammonium are differentially affected by single mutations in the pore mouth of small conductance calcium-activated potassium (SK) channels
Dilly, Sébastien ULg; Philippart, Fabian ULg; Lamy, Cédric et al

in Biochemical Pharmacology (2013), 85

Valine residues in the pore region of SK2 (V366) and SK3 (V520) were replaced by either an alanine or a phenylalanine to evaluate the impact on the interactions with the allosteric blocker apamin. Unlike ... [more ▼]

Valine residues in the pore region of SK2 (V366) and SK3 (V520) were replaced by either an alanine or a phenylalanine to evaluate the impact on the interactions with the allosteric blocker apamin. Unlike TEA which showed high sensitivity to phenylalanine mutated channels, the binding affinity of apamin to the phenylalanine mutants was strongly reduced. In addition, currents from phenylalanine mutants were largely resistant to block by apamin. On the other hand, when the valine residue was replaced by an alanine residue, an increase of the binding affinity and the amount of block by apamin was observed for alanine mutated SK2 channels, but not for mutated SK3 channels. Interestingly, the VA mutation reduced the sensitivity to TEA. In silico data confirmed these experimental results. Therefore, such mutations in the pore region of SK channels show that the three-dimensional structure of the SK tetramers can be disorganized in the outer pore region leading to reduced interaction of apamin with its target. [less ▲]

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See detailA novel phase portrait for neuronal excitability
Drion, Guillaume ULg; Franci, Alessio ULg; Seutin, Vincent ULg et al

in PLoS ONE (2012), 7(8),

Fifty years ago, FitzHugh introduced a phase portrait that became famous for a twofold reason: it captured in a physiological way the qualitative behavior of Hodgkin-Huxley model and it revealed the power ... [more ▼]

Fifty years ago, FitzHugh introduced a phase portrait that became famous for a twofold reason: it captured in a physiological way the qualitative behavior of Hodgkin-Huxley model and it revealed the power of simple dynamical models to unfold complex firing patterns. To date, in spite of the enormous progresses in qualitative and quantitative neural modeling, this phase portrait has remained a core picture of neuronal excitability. Yet, a major difference between the neurophysiology of 1961 and of 2011 is the recognition of the prominent role of calcium channels in firing mechanisms. We show that including this extra current in Hodgkin-Huxley dynamics leads to a revision of FitzHugh-Nagumo phase portrait that affects in a fundamental way the reduced modeling of neural excitability. The revisited model considerably enlarges the modeling power of the original one. In particular, it captures essential electrophysiological signatures that otherwise require non-physiological alteration or considerable complexification of the classical model. As a basic illustration, the new model is shown to highlight a core dynamical mechanism by which calcium channels control the two distinct firing modes of thalamocortical neurons. [less ▲]

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See detailPhysiologie, pharmacologie et modélisation de canaux potassiques : zoom sur les canaux SK
Dilly, Sébastien ULg; Poncin, Sylvie; Lamy, Cédric et al

in Medecine Sciences : M/S (2012), 28

Various types of ion channels are involved in the control of neuronal activity. Among them, SK channels represent an interesting therapeutic target. Indeed, they underlie medium duration ... [more ▼]

Various types of ion channels are involved in the control of neuronal activity. Among them, SK channels represent an interesting therapeutic target. Indeed, they underlie medium duration afterhyperpolarizations in many types of neurons, thus inhibiting cell excitability. A thorough knowledge of the physiology of these channels and the discovery of non-peptidic selective modulators able to pass the blood-brain barrier are essential in view of developing future drugs for brain diseases such as those related to a dysfunction of dopaminergic and serotonergic systems. [less ▲]

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See detailInteractions of apamin with pore mutated SK3 channels
Dilly, Sébastien ULg; Lamy, Cédric; Poncin, Sylvie et al

Poster (2012, March 16)

In the present work, we have tested the impact of the replacement of valine residues in the pore region of SK3 (520) by either an alanine or a phenylalanine residue in terms of the interactions of apamin ... [more ▼]

In the present work, we have tested the impact of the replacement of valine residues in the pore region of SK3 (520) by either an alanine or a phenylalanine residue in terms of the interactions of apamin with these mutants in comparison with the corresponding native channels. Replacing valine residue at position 520 of the SK3 channel by a phenylalanine significantly increased the sensitivity of the channel to be blocked by tetraethylammonium (TEA) as previously reported. Indeed, an aromatic residue, such as a phenylalanine or a tyrosine, is frequently found in the pore region of several potassium channels more sensitive to TEA than SK channels. We measured the affinity (Kd) of apamin in saturation experiments and studied SK currents in transfected cells using patch clamp techniques. In parallel, molecular modelling techniques were used to examine the impact of these local modifications on the interaction of apamin with the corresponding channels. The presence of a phenylalanine in the pore region of potassium channels led to a higher sensitivity for TEA by creating more hydrophobic interactions as found by the docking procedure. In the in vitro binding experiments, the phenylalanine mutant (SK3VF) displayed a very low affinity for apamin. In patch clamp experiments, the SK current was only very partially blocked by apamin in the SK3VF mutant. Furthermore, apamin displayed an affinity and a blocking activity for the alanine mutant close to that for the corresponding native channels. In conclusion, the presence of a bulky and hydrophobic residue at a position near the pore mouth of SK3 channels has a negative impact on their interactions with apamin. [less ▲]

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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 ▲]

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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 ▲]

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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 ▲]

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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

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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 ▲]

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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

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