Characterization of Convergent Suppression by UCL-2077 (3-(Triphenylmethylaminomethyl)pyridine), Known to Inhibit Slow Afterhyperpolarization, of erg-Mediated Potassium Currents and Intermediate-Conductance Calcium-Activated Potassium Channels

Abstract

UCL-2077 (triphenylmethylaminomethyl)pyridine) was previously reported to suppress slow afterhyperpolarization in neurons. However, the information with respect to the effects of UCL-2077 on ionic currents is quite scarce. The addition of UCL-2077 decreased the amplitude of erg-mediated K+ current (IK(erg)) together with an increased deactivation rate of the current in pituitary GH3 cells. The IC50 and KD values of UCL-2077-induced inhibition of IK(erg) were 4.7 and 5.1 μM, respectively. UCL-2077 (10 μM) distinctly shifted the midpoint in the activation curve of IK(erg) to less hyperpolarizing potentials by 17 mV. Its presence decreased the degree of voltage hysteresis for IK(erg) elicitation by long-lasting triangular ramp pulse. It also diminished the probability of the opening of intermediate-conductance Ca2+-activated K+ channels. In cell-attached current recordings, UCL-2077 raised the frequency of action currents. When KCNH2 mRNA was knocked down, a UCL-2077-mediated increase in AC firing was attenuated. Collectively, the actions elaborated herein conceivably contribute to the perturbating effects of this compound on electrical behaviors of excitable cells.

Evidence for the Effectiveness of Remdesivir (GS-5734), a Nucleoside-Analog Antiviral Drug in the Inhibition of IK(M) or IK(DR) and in the Stimulation of IMEP

“…Moreover, the voltage-dependent hysteretic changes of ionic currents are hypothesized to play an essential characteristic in the behaviors of different types of electrically excitable cells. In the current study, echoing previous observations (Männikko et al, 2005;Fürst and D'Avanzo, 2015;Hsu et al, 2020), the I K(M) endogenously in GH 3 cells was also observed to go either through a voltage-dependent hysteresis, or a mode-shift in the conditions of which the voltage sensitivity of gating charge movements is dependent on the previous state. By long-lasting triangular ramp pulse, RDZ noticeably suppressed the strength of voltage-dependent hysteresis for I K(M) elicitation.…”

“…Further, we investigated the potential modifications of RDV on another K + current (i.e., I K(erg) ) also endogenously in these cells. Under our experimental conditions, the deactivating inwardly directed I K(erg) could be robustly elicited from −10 mV holding potential to a range of voltage pulses from −100 to −10 mV within 1 sec ( Wu et al., 2000 ; Huang et al., 2011 ; Hsu et al., 2020 ). When GH 3 cells were exposed to RDV at a concentration of 30 μM, the amplitude of deactivating I K(erg) was mildly but significantly depressed throughout the entire voltage-clamp pulses applied ( Figure 8 ).…”

“…The voltage hysteresis of ionic currents has been demonstrated to have an impact on electrical behaviors of action-potential firing ( Männikko et al., 2005 ; Fürst and D’Avanzo, 2015 ; Hsu et al., 2020 ). The I K(M) amplitude triggered by the upsloping limb of triangular voltage ramp was considerable lower that that by the downsloping limb, strongly indicating a voltage-dependent hysteresis for I K(M) as depicted in Figure 7B , according to the relationship of I K(M) versus membrane voltage.…”

“…The experimental results illustrated that the strength of I K(M) in the upsloping lime was considerably raised as the duration of triangular ramp pulse elevated, while that in the downsloping limb was gradually declined, and that adding RDV contributed to a decline of I K(M) by a time-dependent manner in GH 3 cells. The voltage hysteresis of ionic currents has been demonstrated to have an impact on electrical behaviors of action-potential firing (Männikko et al, 2005;Fürst and D'Avanzo, 2015;Hsu et al, 2020). The I K(M) amplitude triggered by the upsloping limb of triangular voltage ramp was considerable lower that that by the downsloping limb, strongly indicating a voltage-dependent hysteresis for I K(M) as depicted in Figure 7B, according to the relationship of I K(M) versus membrane voltage.…”

Effects of Sesamin, the Major Furofuran Lignan of Sesame Oil, on the Amplitude and Gating of Voltage-Gated Na+ and K+ Currents

“…We further explored whether SSM could perturb another types of K + currents (i.e., I K(erg) and I K(DR) ) in these cells. As demonstrated previously [ 15 , 23 , 37 ], to amplify the deactivated I K(erg) , cells were bathed in high-K + , Ca 2+ -free solution. In this stage of the measurements, we bathed cells in high-K + , Ca 2+ -free solution containing 1 μM tetrodotoxin (TTX), and then filled up the electrodes by using K + -enriched solution.…”