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Jun Ho Lee - One of the best experts on this subject based on the ideXlab platform.

  • Molecular basis involved in the blocking effect of antidepressant Metergoline on C-type inactivation of Kv1.4 channel.
    Neuropharmacology, 2019
    Co-Authors: Hyoung-woo Bai, Hye Duck Yeom, Sanung Eom, Khoa V.a. Nguyen, Jaeeun Lee, Sung-oh Sohn, Jun Ho Lee
    Abstract:

    Abstract Voltage-gated potassium channels (VGKCs) are transmembrane ion channels specific for potassium. Currently there are nine kinds of VGKCs. Kv1.4 is one of shaker-related potassium channels. It is a representative alpha subunit of potassium channels that can inactivate A type-currents, leading to N pattern inactivation. Inactivation of Kv channels plays an important role in shaping electrical signaling properties of neuronal and muscular cells. The shape of N pattern inactivation can be modified by removing the N-terminal (NT) domain which results in non-inactivated currents and C pattern inactivation. In a previous work, we have reported the regulatory effect of Metergoline on Kv1.4 and Nav1.2 channel activity. In the present study, we constructed a mutant of deleted 61 residues from NT of Kv1.4 channels (Kv1.4 Δ2-61) and found that it induced an outward peak and steady-state currents We also studied the modulation effect of Metergoline on the activity of this Kv1.4 Δ2-61 mutant channel without having the N-terminal quick inactivation domain. Our results revealed that treatment with Metergoline inhibited NT deleted Kv1.4 mutant channel activity in a concentration-dependent manner which was reversible. Interestingly, Metergoline treatment induced little effects on the outward peak current in the deleted Kv1.4 mutant channel. However, Metergoline treatment conspicuously inhibited steady state currents of Kv1.4 Δ2-61 channels with acceleration current mode. The acceleration of steady-state current of deleted Kv1.4 mutant channel occurred in a concentration-dependent manner. This means that Metergoline can accelerate C pattern inactivation of Kv1.4 Δ2-61 channel by acting as an open state dependent channel blocker. We also performed site-directed mutations in V561A and K532Y, also known as C-type inactivation sites. V561A, K532Y, and V561A + K532Y substitution mutants significantly attenuated the acceleration effect of Metergoline on C pattern inactivation of hKv1.4 channel currents. In docking modeling study, predicted binding residues for Metergoline were analyzed for six amino acids. Among them, the K532 residue known as the C-type inactivation site was analyzed to be a major site of action. Then various mutants were constructed. K532 substitution mutant significantly abolished the effect of Metergoline on Kv1.4 currents among various mutants whereas other changes had slight inhibitory effects. Furthermore, we found that Metergoline had specificity for Kv1.4, but not for Kv1.5 currents. In addition, the A type current in rat neuronal cell was inhibited and accelerated of inactivation. This result further shows that Metergoline might interact with Lys532 residue and then accelerate C pattern inactivation of Kv1.4 channels with channel type specificity. Taken together, these results demonstrate the molecular basis involved in the effect of Metergoline, an ergot alkaloid, on human Kv1.4 channel, providing a novel interaction ligand.

  • Regulation of Human Kv1.4 Channel Activity by the Antidepressant Metergoline
    Biological & Pharmaceutical Bulletin, 2016
    Co-Authors: Hye Duck Yeom, Jun Ho Lee
    Abstract:

    Metergoline is an ergot-derived psychoactive drug that is a ligand for various serotonin and dopamine receptors. Little is known about the effect of Metergoline on different types of receptors and ion channels. Potassium channels are the most diverse group of ion channels. Kv1.4, a shaker family K channel alpha subunit, is one of a family of voltage gated K channels that mediates transient and rapid inactivating A-type currents and N-type inactivation. We demonstrated previously that Metergoline inhibited the activity of neuronal voltage-dependent Na(+) channels in Xenopus laevis oocytes (Acta Pharmacol. Sin., 35, 2014, Lee et al.). In this study, we sought to elucidate the regulatory effects underlying Metergoline-induced human Kv1.4 channel inhibition. We used the two electrode voltage-clamp (TEVC) technique to investigate the effect of Metergoline on human Kv1.4 channel currents in Xenopus laevis oocytes expressing human Kv1.4 alpha subunits. Interestingly, Metergoline treatment also induced inhibition of peak currents in human Kv1.4 channels in a concentration-dependent manner. The IC50 of peak currents of hKv1.4 currents was 3.6±0.6 µM. These results indicate that Metergoline might regulate the human Kv1.4 channel activity that is expressed in X. laevis oocytes. Further, this regulation of potassium currents by Metergoline might be one of the pharmacological actions of Metergoline-mediated psychoactivity.

  • Metergoline inhibits the neuronal Nav1.2 voltage-dependent Na(+) channels expressed in Xenopus oocytes.
    Acta Pharmacologica Sinica, 2014
    Co-Authors: Jun Ho Lee, Minkyu Shin, Moochang Hong, Jian Liu, Seung-yeol Nah, Hyunsu Bae
    Abstract:

    Metergoline inhibits the neuronal Nav1.2 voltage-dependent Na + channels expressed in Xenopus oocytes

  • Metergoline inhibits the neuronal nav1 2 voltage dependent na channels expressed in xenopus oocytes
    Acta Pharmacologica Sinica, 2014
    Co-Authors: Jun Ho Lee, Minkyu Shin, Moochang Hong, Jian Liu, Seung-yeol Nah, Hyunsu Bae
    Abstract:

    Metergoline inhibits the neuronal Nav1.2 voltage-dependent Na + channels expressed in Xenopus oocytes

Moochang Hong - One of the best experts on this subject based on the ideXlab platform.

  • Metergoline inhibits the neuronal Nav1.2 voltage-dependent Na^+ channels expressed in Xenopus oocytes
    Acta Pharmacologica Sinica, 2014
    Co-Authors: Minkyu Shin, Moochang Hong
    Abstract:

    Aim: Metergoline is an ergot-derived psychoactive drug that acts as a ligand for serotonin and dopamine receptors. The aim of this study was to investigate the regulatory effects of Metergoline on the neuronal Nav1.2 voltage-dependent Na^+ channels in vitro . Methods: Xenopus oocytes were injected with cRNAs encoding rat brain Nav1.2 α and β1 subunits. Voltage-activated Na^+ currents were recorded using two-electrode voltage clamp technique. Drugs were applied though perfusion. Results: Both Metergoline and lidocaine reversibly and concentration-dependently inhibited the peak of Na^+ currents with IC_50 values of 3.6±4.2 and 916.9±98.8 μmol/L, respectively. Metergoline (3 μmol/L) caused a 6.8±1.2 mV depolarizing shift of the steady-state activation curve of the Na^+ currents, and did not alter the inactivation curve. In contrast, lidocaine (3 μmol/L) caused a 12.7±1.2 mV hyperpolarizing shift of the inactivation curve of the Na^+ currents without changing the steady-state activation curve. Both Metergoline and lidocaine produced tonic and use-dependent inhibition on the peak of Na^+ currents. Conclusion: Metergoline exerts potent inhibition on the activity of neuronal Nav1.2 channels, which may contribute to its actions on the central nervous system.

  • Metergoline inhibits the neuronal Nav1.2 voltage-dependent Na(+) channels expressed in Xenopus oocytes.
    Acta Pharmacologica Sinica, 2014
    Co-Authors: Jun Ho Lee, Minkyu Shin, Moochang Hong, Jian Liu, Seung-yeol Nah, Hyunsu Bae
    Abstract:

    Metergoline inhibits the neuronal Nav1.2 voltage-dependent Na + channels expressed in Xenopus oocytes

  • Metergoline inhibits the neuronal nav1 2 voltage dependent na channels expressed in xenopus oocytes
    Acta Pharmacologica Sinica, 2014
    Co-Authors: Jun Ho Lee, Minkyu Shin, Moochang Hong, Jian Liu, Seung-yeol Nah, Hyunsu Bae
    Abstract:

    Metergoline inhibits the neuronal Nav1.2 voltage-dependent Na + channels expressed in Xenopus oocytes

Hyunsu Bae - One of the best experts on this subject based on the ideXlab platform.

Sarah De Saeger - One of the best experts on this subject based on the ideXlab platform.

  • Molecularly imprinted polymers immobilized on 3D printed scaffolds as novel solid phase extraction sorbent for Metergoline.
    Analytica Chimica Acta, 2017
    Co-Authors: Gilke De Middeleer, Peter Dubruel, Sarah De Saeger
    Abstract:

    Abstract In the present work, a novel solid phase extraction (SPE) sorbent was developed based on molecularly imprinted polymers (MIPs) immobilized on 3D-printed scaffolds using polymer networks as MIP-immobilizing layer. MIPs were produced by precipitation polymerization in acetonitrile (ACN) using methacrylic acid (MAA) as functional monomer, trimethylolpropane trimethacrylate (TRIM) as crosslinker and Metergoline as model template which allows final recognition of ergot alkaloid mycotoxins. Scanning electron microscopy (SEM) and dynamic light scattering (DLS) analyses showed an average MIP particle size of 457 ± 145 nm. Functional MIP analysis revealed dissociation constants (K D ) of 0.29 and 38.90 μM for high and low affinity binding sites respectively. Subsequently, crosslinking of polymer network building blocks was applied as MIP immobilization method on poly-e-caprolactone (PCL) which was selected as polymer model. Methodology optimization and subsequent evaluation were first realized on 2D PCL surfaces. Based on analyses such as optical evaluation of MIP availability after immobilization through SEM and depth profilometry, an optimal polymer network building block concentration of 7.5 w/w% was selected. In a final part, transfer of MIP immobilization to 3D PCL scaffolds was successfully realized. Functional analysis showed that the newly developed SPE sorbents were able to rebind 44.87 ± 8.30% of a 1 μM Metergoline solution. In conclusion, a new type of SPE sorbent was developed for the detection of Metergoline by the use of MIP-functionalized polymer scaffolds. The applied technology opens up future possibilities for the extraction of a broad range of components such as other mycotoxins.

  • development of suspension polymerized molecularly imprinted beads with Metergoline as template and application in a solid phase extraction procedure toward ergot alkaloids
    Analytical Chemistry, 2012
    Co-Authors: Pieterjan Lenain, Jose Diana Di Mavungu, Peter Dubruel, Johan Robbens, Sarah De Saeger
    Abstract:

    The first successfully developed molecularly imprinted polymer toward six ergot alkaloids and their respective epimers is described. A new imprinting molecule, Metergoline, was used as template analogue in the production of suspension polymerized beads. These spherical particles functioned as selective sorbent in a solid-phase extraction column. The application of this column in the cleanup of barley samples prior to liquid chromatography coupled with tandem mass spectrometry allowed simple and cost-efficient sample preparation. The performance of the imprinted polymer and a non-imprinted control polymer was evaluated. This includes determination of the recovery values and the matrix effect of each of the 12 tested ergot alkaloids as well as a cross-reactivity study with 25 common mycotoxins. The binding isotherms were obtained for Metergoline, thus allowing comparison with other (imprinted) sorbents. A comparison between bulk and suspension polymerization is provided to determine the appropriate producti...

Minkyu Shin - One of the best experts on this subject based on the ideXlab platform.

  • Metergoline inhibits the neuronal Nav1.2 voltage-dependent Na^+ channels expressed in Xenopus oocytes
    Acta Pharmacologica Sinica, 2014
    Co-Authors: Minkyu Shin, Moochang Hong
    Abstract:

    Aim: Metergoline is an ergot-derived psychoactive drug that acts as a ligand for serotonin and dopamine receptors. The aim of this study was to investigate the regulatory effects of Metergoline on the neuronal Nav1.2 voltage-dependent Na^+ channels in vitro . Methods: Xenopus oocytes were injected with cRNAs encoding rat brain Nav1.2 α and β1 subunits. Voltage-activated Na^+ currents were recorded using two-electrode voltage clamp technique. Drugs were applied though perfusion. Results: Both Metergoline and lidocaine reversibly and concentration-dependently inhibited the peak of Na^+ currents with IC_50 values of 3.6±4.2 and 916.9±98.8 μmol/L, respectively. Metergoline (3 μmol/L) caused a 6.8±1.2 mV depolarizing shift of the steady-state activation curve of the Na^+ currents, and did not alter the inactivation curve. In contrast, lidocaine (3 μmol/L) caused a 12.7±1.2 mV hyperpolarizing shift of the inactivation curve of the Na^+ currents without changing the steady-state activation curve. Both Metergoline and lidocaine produced tonic and use-dependent inhibition on the peak of Na^+ currents. Conclusion: Metergoline exerts potent inhibition on the activity of neuronal Nav1.2 channels, which may contribute to its actions on the central nervous system.

  • Metergoline inhibits the neuronal Nav1.2 voltage-dependent Na(+) channels expressed in Xenopus oocytes.
    Acta Pharmacologica Sinica, 2014
    Co-Authors: Jun Ho Lee, Minkyu Shin, Moochang Hong, Jian Liu, Seung-yeol Nah, Hyunsu Bae
    Abstract:

    Metergoline inhibits the neuronal Nav1.2 voltage-dependent Na + channels expressed in Xenopus oocytes

  • Metergoline inhibits the neuronal nav1 2 voltage dependent na channels expressed in xenopus oocytes
    Acta Pharmacologica Sinica, 2014
    Co-Authors: Jun Ho Lee, Minkyu Shin, Moochang Hong, Jian Liu, Seung-yeol Nah, Hyunsu Bae
    Abstract:

    Metergoline inhibits the neuronal Nav1.2 voltage-dependent Na + channels expressed in Xenopus oocytes