High Efficacy by GAL-021: A Known Intravenous Peripheral Chemoreceptor Modulator that Suppresses BK<sub>Ca</sub>-Channel Activity and Inhibits <i>I</i><sub>K(M)</sub> or <i>I</i><sub>h</sub>
GAL-021 has recently been developed as a novel breathing control modulator. However, modifications of ionic currents produced by this agent remain uncertain, although its efficacy in suppressing the activity of big-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> (BK<su...
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doaj-7247e4c988f541f69200dd439d464f882020-11-25T03:32:00ZengMDPI AGBiomolecules2218-273X2020-01-0110218810.3390/biom10020188biom10020188High Efficacy by GAL-021: A Known Intravenous Peripheral Chemoreceptor Modulator that Suppresses BK<sub>Ca</sub>-Channel Activity and Inhibits <i>I</i><sub>K(M)</sub> or <i>I</i><sub>h</sub>Te-Ling Lu0Zi-Han Gao1Shih-Wei Li2Sheng-Nan Wu3School of Pharmacy, China Medical University, Taichung City 40402, TaiwanDepartment of Physiology, National Cheng Kung University Medical College, Tainan City 70101, TaiwanDepartment of Physiology, National Cheng Kung University Medical College, Tainan City 70101, TaiwanDepartment of Physiology, National Cheng Kung University Medical College, Tainan City 70101, TaiwanGAL-021 has recently been developed as a novel breathing control modulator. However, modifications of ionic currents produced by this agent remain uncertain, although its efficacy in suppressing the activity of big-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> (BK<sub>Ca</sub>) channels has been reported. In pituitary tumor (GH<sub>3</sub>) cells, we found that the presence of GAL-021 decreased the amplitude of macroscopic Ca<sup>2+</sup>-activated K<sup>+</sup> current (<i>I</i><sub>K(Ca)</sub>) in a concentration-dependent manner with an effective IC<sub>50</sub> of 2.33 μM. GAL-021-mediated reduction of <i>I</i><sub>K(Ca)</sub> was reversed by subsequent application of verteporfin or ionomycin; however, it was not by that of diazoxide. In inside-out current recordings, the addition of GAL-021 to the bath markedly decreased the open-state probability of BK<sub>Ca</sub> channels. This agent also resulted in a rightward shift in voltage dependence of the activation curve of BK<sub>Ca</sub> channels; however, neither the gating charge of the curve nor single-channel conductance of the channel was changed. There was an evident lengthening of the mean closed time of BK<sub>Ca</sub> channels in the presence of GAL-021, with no change in mean open time. The GAL-021 addition also suppressed M-type K<sup>+</sup> current with an effective IC<sub>50</sub> of 3.75 μM; however, its presence did not alter the amplitude of <i>erg</i>-mediated K<sup>+</sup> current, or mildly suppressed delayed-rectifier K<sup>+</sup> current. GAL-021 at a concentration of 30 μM could also suppress hyperpolarization-activated cationic current. In HEK293T cells expressing <i>α-hSlo</i>, the addition of GAL-021 was also able to suppress the BK<sub>Ca</sub>-channel open probabilities, and GAL-021-mediated suppression of BK<sub>Ca</sub>-channel activity was attenuated by further addition of BMS-191011. Collectively, the GAL-021 effects presented herein do not exclusively act on BK<sub>Ca</sub> channels and these modifications on ionic currents exert significant influence on the functional activities of electrically excitable cells occurring in vivo.https://www.mdpi.com/2218-273X/10/2/188gal-021ca<sup>2+</sup>-activated k<sup>+</sup> currentlarge-conductance ca<sup>2+</sup>-activated k<sup>+</sup> channelm-type k<sup>+</sup> currentpituitary tumor cells<i>α-hslo</i> |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Te-Ling Lu Zi-Han Gao Shih-Wei Li Sheng-Nan Wu |
spellingShingle |
Te-Ling Lu Zi-Han Gao Shih-Wei Li Sheng-Nan Wu High Efficacy by GAL-021: A Known Intravenous Peripheral Chemoreceptor Modulator that Suppresses BK<sub>Ca</sub>-Channel Activity and Inhibits <i>I</i><sub>K(M)</sub> or <i>I</i><sub>h</sub> Biomolecules gal-021 ca<sup>2+</sup>-activated k<sup>+</sup> current large-conductance ca<sup>2+</sup>-activated k<sup>+</sup> channel m-type k<sup>+</sup> current pituitary tumor cells <i>α-hslo</i> |
author_facet |
Te-Ling Lu Zi-Han Gao Shih-Wei Li Sheng-Nan Wu |
author_sort |
Te-Ling Lu |
title |
High Efficacy by GAL-021: A Known Intravenous Peripheral Chemoreceptor Modulator that Suppresses BK<sub>Ca</sub>-Channel Activity and Inhibits <i>I</i><sub>K(M)</sub> or <i>I</i><sub>h</sub> |
title_short |
High Efficacy by GAL-021: A Known Intravenous Peripheral Chemoreceptor Modulator that Suppresses BK<sub>Ca</sub>-Channel Activity and Inhibits <i>I</i><sub>K(M)</sub> or <i>I</i><sub>h</sub> |
title_full |
High Efficacy by GAL-021: A Known Intravenous Peripheral Chemoreceptor Modulator that Suppresses BK<sub>Ca</sub>-Channel Activity and Inhibits <i>I</i><sub>K(M)</sub> or <i>I</i><sub>h</sub> |
title_fullStr |
High Efficacy by GAL-021: A Known Intravenous Peripheral Chemoreceptor Modulator that Suppresses BK<sub>Ca</sub>-Channel Activity and Inhibits <i>I</i><sub>K(M)</sub> or <i>I</i><sub>h</sub> |
title_full_unstemmed |
High Efficacy by GAL-021: A Known Intravenous Peripheral Chemoreceptor Modulator that Suppresses BK<sub>Ca</sub>-Channel Activity and Inhibits <i>I</i><sub>K(M)</sub> or <i>I</i><sub>h</sub> |
title_sort |
high efficacy by gal-021: a known intravenous peripheral chemoreceptor modulator that suppresses bk<sub>ca</sub>-channel activity and inhibits <i>i</i><sub>k(m)</sub> or <i>i</i><sub>h</sub> |
publisher |
MDPI AG |
series |
Biomolecules |
issn |
2218-273X |
publishDate |
2020-01-01 |
description |
GAL-021 has recently been developed as a novel breathing control modulator. However, modifications of ionic currents produced by this agent remain uncertain, although its efficacy in suppressing the activity of big-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> (BK<sub>Ca</sub>) channels has been reported. In pituitary tumor (GH<sub>3</sub>) cells, we found that the presence of GAL-021 decreased the amplitude of macroscopic Ca<sup>2+</sup>-activated K<sup>+</sup> current (<i>I</i><sub>K(Ca)</sub>) in a concentration-dependent manner with an effective IC<sub>50</sub> of 2.33 μM. GAL-021-mediated reduction of <i>I</i><sub>K(Ca)</sub> was reversed by subsequent application of verteporfin or ionomycin; however, it was not by that of diazoxide. In inside-out current recordings, the addition of GAL-021 to the bath markedly decreased the open-state probability of BK<sub>Ca</sub> channels. This agent also resulted in a rightward shift in voltage dependence of the activation curve of BK<sub>Ca</sub> channels; however, neither the gating charge of the curve nor single-channel conductance of the channel was changed. There was an evident lengthening of the mean closed time of BK<sub>Ca</sub> channels in the presence of GAL-021, with no change in mean open time. The GAL-021 addition also suppressed M-type K<sup>+</sup> current with an effective IC<sub>50</sub> of 3.75 μM; however, its presence did not alter the amplitude of <i>erg</i>-mediated K<sup>+</sup> current, or mildly suppressed delayed-rectifier K<sup>+</sup> current. GAL-021 at a concentration of 30 μM could also suppress hyperpolarization-activated cationic current. In HEK293T cells expressing <i>α-hSlo</i>, the addition of GAL-021 was also able to suppress the BK<sub>Ca</sub>-channel open probabilities, and GAL-021-mediated suppression of BK<sub>Ca</sub>-channel activity was attenuated by further addition of BMS-191011. Collectively, the GAL-021 effects presented herein do not exclusively act on BK<sub>Ca</sub> channels and these modifications on ionic currents exert significant influence on the functional activities of electrically excitable cells occurring in vivo. |
topic |
gal-021 ca<sup>2+</sup>-activated k<sup>+</sup> current large-conductance ca<sup>2+</sup>-activated k<sup>+</sup> channel m-type k<sup>+</sup> current pituitary tumor cells <i>α-hslo</i> |
url |
https://www.mdpi.com/2218-273X/10/2/188 |
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