Stimulatory actions of a novel thiourea derivative on large-conductance, calcium-activated potassium channels
| Autor: | Hwei Hisen Chen, Chih Chin Lee, Jyh-Haur Chern, Ying Ting Hsu, Ming Chi Lai, Feng Shiun Shie, Sheng Nan Wu, Ming-Huan Chan, Santai Shen |
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| Rok vydání: | 2017 |
| Předmět: |
Lipopolysaccharides
0301 basic medicine Physiology Interleukin-1beta Clinical Biochemistry Anti-Inflammatory Agents Nitric Oxide Synthase Type II Gating Transfection Inhibitory postsynaptic potential Membrane Potentials 03 medical and health sciences chemistry.chemical_compound Tolbutamide Cell Line Tumor medicine Animals Humans Pituitary Neoplasms Calcium Signaling Large-Conductance Calcium-Activated Potassium Channel alpha Subunits Ion channel Mice Inbred BALB C Dose-Response Relationship Drug biology Chemistry Thiourea Conductance Cell Biology Calcium-activated potassium channel Rats Nitric oxide synthase Calcium Channel Agonists Kinetics HEK293 Cells 030104 developmental biology biology.protein Biophysics Calcium Microglia Ion Channel Gating medicine.drug |
| Zdroj: | Journal of Cellular Physiology. 232:3409-3421 |
| ISSN: | 0021-9541 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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