High Efficacy by GAL-021: A Known Intravenous Peripheral Chemoreceptor Modulator that Suppresses BK_Ca-Channel Activity and Inhibits <i>I</i>_K(M) or <i>I</i>_h

• Main Authors: Te-Ling Lu, Zi-Han Gao, Shih-Wei Li, Sheng-Nan Wu
• Format: Article
• Language: English
• Published: MDPI AG 2020-01-01
• Series: Biomolecules
• Subjects: gal-021; ca²⁺-activated k⁺ current; large-conductance ca²⁺-activated k⁺ channel; m-type k⁺ current; pituitary tumor cells; <i>α-hslo</i>
• Online Access: https://www.mdpi.com/2218-273X/10/2/188

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 Ca²⁺-activated K⁺ (BK_Ca) channels has been reported. In pituitary tumor (GH₃) cells, we found that the presence of GAL-021 decreased the amplitude of macroscopic Ca²⁺-activated K⁺ current (<i>I</i>_K(Ca)) in a concentration-dependent manner with an effective IC₅₀ of 2.33 &#956;M. GAL-021-mediated reduction of <i>I</i>_K(Ca) 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_Ca channels. This agent also resulted in a rightward shift in voltage dependence of the activation curve of BK_Ca 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_Ca channels in the presence of GAL-021, with no change in mean open time. The GAL-021 addition also suppressed M-type K⁺ current with an effective IC₅₀ of 3.75 &#956;M; however, its presence did not alter the amplitude of <i>erg</i>-mediated K⁺ current, or mildly suppressed delayed-rectifier K⁺ current. GAL-021 at a concentration of 30 &#956;M could also suppress hyperpolarization-activated cationic current. In HEK293T cells expressing <i>&#945;-hSlo</i>, the addition of GAL-021 was also able to suppress the BK_Ca-channel open probabilities, and GAL-021-mediated suppression of BK_Ca-channel activity was attenuated by further addition of BMS-191011. Collectively, the GAL-021 effects presented herein do not exclusively act on BK_Ca channels and these modifications on ionic currents exert significant influence on the functional activities of electrically excitable cells occurring in vivo.