Stimulatory actions of a novel thiourea derivative on large-conductance, calcium-activated potassium channels

Sheng-Nan Wu, Jyh Haur Chern, Santai Shen, Hwei Hisen Chen, Ying Ting Hsu, Chih Chin Lee, Ming Huan Chan, Ming Chi Lai, Feng Shiun Shie

Research output: Contribution to journalArticle

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Abstract

In this study, we examine whether an anti-inflammatory thiourea derivative, compound #326, actions on ion channels. The effects of compound #326 on Ca2+-activated K+ channels were evaluated by patch-clamp recordings obtained in cell-attached, inside-out or whole-cell configuration. In pituitary GH3 cells, compound #326 increased the amplitude of Ca2+-activated K+ currents (IK(Ca)) with an EC50 value of 11.6 μM, which was reversed by verruculogen, but not tolbutamide or TRAM-34. Under inside-out configuration, a bath application of compound #326 raised the probability of large-conductance Ca2+-activated K+ (BKCa) channels. The activation curve of BKCa channels was shifted to less depolarised potential with no modification of the gating charge of the curve; consequently, the difference of free energy was reduced in the presence of this compound. Compound #326-stimulated activity of BKCa channels is explained by a shortening of mean closed time, despite its inability to alter single-channel conductance. Neither delayed-rectifier nor erg-mediated K+ currents was modified. Compound #326 decreased the peak amplitude of voltage-gated Na+ current with no clear change in the overall current–voltage relationship of this current. In HEK293T cells expressing α-hSlo, compound #326 enhanced BKCa channels effectively. Intriguingly, the inhibitory actions of compound #326 on interleukin 1β in lipopolysaccharide-activated microglia were significantly reversed by verruculogen, whereas BKCa channel inhibitors suppressed the expressions of inducible nitric oxide synthase. The BKCa channels could be an important target for compound #326 if similar in vivo results occur, and the multi-functionality of BKCa channels in modulating microglial immunity merit further investigation.

Original languageEnglish
Pages (from-to)3409-3421
Number of pages13
JournalJournal of Cellular Physiology
Volume232
Issue number12
DOIs
Publication statusPublished - 2017 Dec 1

Fingerprint

Large-Conductance Calcium-Activated Potassium Channels
Thiourea
Derivatives
Calcium-Activated Potassium Channels
Tolbutamide
Clamping devices
Nitric Oxide Synthase Type II
Interleukin-1
Ion Channels
Free energy
Lipopolysaccharides
Anti-Inflammatory Agents
Chemical activation
Cells
Microglia
Electric potential
Baths
Immunity
verruculogen
TRAM 34

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Wu, Sheng-Nan ; Chern, Jyh Haur ; Shen, Santai ; Chen, Hwei Hisen ; Hsu, Ying Ting ; Lee, Chih Chin ; Chan, Ming Huan ; Lai, Ming Chi ; Shie, Feng Shiun. / Stimulatory actions of a novel thiourea derivative on large-conductance, calcium-activated potassium channels. In: Journal of Cellular Physiology. 2017 ; Vol. 232, No. 12. pp. 3409-3421.
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abstract = "In this study, we examine whether an anti-inflammatory thiourea derivative, compound #326, actions on ion channels. The effects of compound #326 on Ca2+-activated K+ channels were evaluated by patch-clamp recordings obtained in cell-attached, inside-out or whole-cell configuration. In pituitary GH3 cells, compound #326 increased the amplitude of Ca2+-activated K+ currents (IK(Ca)) with an EC50 value of 11.6 μM, which was reversed by verruculogen, but not tolbutamide or TRAM-34. Under inside-out configuration, a bath application of compound #326 raised the probability of large-conductance Ca2+-activated K+ (BKCa) channels. The activation curve of BKCa channels was shifted to less depolarised potential with no modification of the gating charge of the curve; consequently, the difference of free energy was reduced in the presence of this compound. Compound #326-stimulated activity of BKCa channels is explained by a shortening of mean closed time, despite its inability to alter single-channel conductance. Neither delayed-rectifier nor erg-mediated K+ currents was modified. Compound #326 decreased the peak amplitude of voltage-gated Na+ current with no clear change in the overall current–voltage relationship of this current. In HEK293T cells expressing α-hSlo, compound #326 enhanced BKCa channels effectively. Intriguingly, the inhibitory actions of compound #326 on interleukin 1β in lipopolysaccharide-activated microglia were significantly reversed by verruculogen, whereas BKCa channel inhibitors suppressed the expressions of inducible nitric oxide synthase. The BKCa channels could be an important target for compound #326 if similar in vivo results occur, and the multi-functionality of BKCa channels in modulating microglial immunity merit further investigation.",
author = "Sheng-Nan Wu and Chern, {Jyh Haur} and Santai Shen and Chen, {Hwei Hisen} and Hsu, {Ying Ting} and Lee, {Chih Chin} and Chan, {Ming Huan} and Lai, {Ming Chi} and Shie, {Feng Shiun}",
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Wu, S-N, Chern, JH, Shen, S, Chen, HH, Hsu, YT, Lee, CC, Chan, MH, Lai, MC & Shie, FS 2017, 'Stimulatory actions of a novel thiourea derivative on large-conductance, calcium-activated potassium channels', Journal of Cellular Physiology, vol. 232, no. 12, pp. 3409-3421. https://doi.org/10.1002/jcp.25788

Stimulatory actions of a novel thiourea derivative on large-conductance, calcium-activated potassium channels. / Wu, Sheng-Nan; Chern, Jyh Haur; Shen, Santai; Chen, Hwei Hisen; Hsu, Ying Ting; Lee, Chih Chin; Chan, Ming Huan; Lai, Ming Chi; Shie, Feng Shiun.

In: Journal of Cellular Physiology, Vol. 232, No. 12, 01.12.2017, p. 3409-3421.

Research output: Contribution to journalArticle

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T1 - Stimulatory actions of a novel thiourea derivative on large-conductance, calcium-activated potassium channels

AU - Wu, Sheng-Nan

AU - Chern, Jyh Haur

AU - Shen, Santai

AU - Chen, Hwei Hisen

AU - Hsu, Ying Ting

AU - Lee, Chih Chin

AU - Chan, Ming Huan

AU - Lai, Ming Chi

AU - Shie, Feng Shiun

PY - 2017/12/1

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N2 - In this study, we examine whether an anti-inflammatory thiourea derivative, compound #326, actions on ion channels. The effects of compound #326 on Ca2+-activated K+ channels were evaluated by patch-clamp recordings obtained in cell-attached, inside-out or whole-cell configuration. In pituitary GH3 cells, compound #326 increased the amplitude of Ca2+-activated K+ currents (IK(Ca)) with an EC50 value of 11.6 μM, which was reversed by verruculogen, but not tolbutamide or TRAM-34. Under inside-out configuration, a bath application of compound #326 raised the probability of large-conductance Ca2+-activated K+ (BKCa) channels. The activation curve of BKCa channels was shifted to less depolarised potential with no modification of the gating charge of the curve; consequently, the difference of free energy was reduced in the presence of this compound. Compound #326-stimulated activity of BKCa channels is explained by a shortening of mean closed time, despite its inability to alter single-channel conductance. Neither delayed-rectifier nor erg-mediated K+ currents was modified. Compound #326 decreased the peak amplitude of voltage-gated Na+ current with no clear change in the overall current–voltage relationship of this current. In HEK293T cells expressing α-hSlo, compound #326 enhanced BKCa channels effectively. Intriguingly, the inhibitory actions of compound #326 on interleukin 1β in lipopolysaccharide-activated microglia were significantly reversed by verruculogen, whereas BKCa channel inhibitors suppressed the expressions of inducible nitric oxide synthase. The BKCa channels could be an important target for compound #326 if similar in vivo results occur, and the multi-functionality of BKCa channels in modulating microglial immunity merit further investigation.

AB - In this study, we examine whether an anti-inflammatory thiourea derivative, compound #326, actions on ion channels. The effects of compound #326 on Ca2+-activated K+ channels were evaluated by patch-clamp recordings obtained in cell-attached, inside-out or whole-cell configuration. In pituitary GH3 cells, compound #326 increased the amplitude of Ca2+-activated K+ currents (IK(Ca)) with an EC50 value of 11.6 μM, which was reversed by verruculogen, but not tolbutamide or TRAM-34. Under inside-out configuration, a bath application of compound #326 raised the probability of large-conductance Ca2+-activated K+ (BKCa) channels. The activation curve of BKCa channels was shifted to less depolarised potential with no modification of the gating charge of the curve; consequently, the difference of free energy was reduced in the presence of this compound. Compound #326-stimulated activity of BKCa channels is explained by a shortening of mean closed time, despite its inability to alter single-channel conductance. Neither delayed-rectifier nor erg-mediated K+ currents was modified. Compound #326 decreased the peak amplitude of voltage-gated Na+ current with no clear change in the overall current–voltage relationship of this current. In HEK293T cells expressing α-hSlo, compound #326 enhanced BKCa channels effectively. Intriguingly, the inhibitory actions of compound #326 on interleukin 1β in lipopolysaccharide-activated microglia were significantly reversed by verruculogen, whereas BKCa channel inhibitors suppressed the expressions of inducible nitric oxide synthase. The BKCa channels could be an important target for compound #326 if similar in vivo results occur, and the multi-functionality of BKCa channels in modulating microglial immunity merit further investigation.

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