Effectiveness in the Block by Honokiol, a Dimerized Allylphenol from Magnolia Officinalis, of Hyperpolarization-Activated Cation Current and Delayed-Rectifier K+ Current

Abstract

Background: Honokiol (HNK), a dimer of allylphenol obtained from the bark of Magnolia officinalis was demonstrated to exert an array of biological actions in different excitable cell types. However, whether or how this compound can lead to any perturbations on surface–membrane ionic currents remains largely unknown. Methods: We used the patch clamp method and found that addition of HNK effectively depressed the density of macroscopic hyperpolarization-activated cation currents (Ih) in pituitary GH3 cells in a concentration-, time- and voltage-dependent manner. By the use of a two-step voltage protocol, the presence of HNK (10 μM) shifted the steady-state activation curve of Ih density along the voltage axis to a more negative potential by approximately 11 mV, together with no noteworthy modification in the gating charge of the current. Results: The voltage-dependent hysteresis of Ih density elicited by long-lasting triangular ramp pulse was attenuated by the presence of HNK. The HNK addition also diminished the magnitude of deactivating Ih density elicited by ramp-up depolarization with varying durations. The effective half-maximal concentration (IC50) value needed to inhibit the density of Ih or delayed rectifier K+ current identified in GH3 cells was estimated to be 2.1 or 6.8 μM, respectively. In cell-attached current recordings, HNK decreased the frequency of spontaneous action currents. In Rolf B1.T olfactory sensory neurons, HNK was also observed to decrease Ih density in a concentration-dependent manner. Conclusions: The present study highlights the evidence revealing that HNK has the propensity to perturb these ionic currents and that the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel is proposed to be a potential target for the in vivo actions of HNK and its structurally similar compounds.

Insulin acts as an atypical KCNQ1/KCNE1‐current activator and reverses long QT in insulin‐resistant aged rats by accelerating the ventricular action potential repolarization through affecting the β3‐adrenergic receptor signaling pathway

“…Our further investigation strongly supported the hypothesis on the contribution of depressed I Ks on the prolonged APD in the aged cardiomyocytes. Our data are in line with previously published data: Indeed, studies have shown that the changes in a slow delayed rectifier channel can contribute to AP repolarization (Marx et al, 2002) and among them, a type of K + -channel, carrying slow outward K + -current, I KS , can contribute to the induction of prolonged APD, further leading to further cardiac arrhythmias through long-QT (Abbott, 2020;Chan et al, 2020;Huang et al, 2018;Wu & Sanguinetti, 2016). Similar findings in vivo PKG inhibitor applied aged rat cardiomyocytes were determined, as well.…”

“…As the changes in a slow delayed rectifier channel can contribute to AP repolarization (Marx et al, 2002) and among them, a type of K + ‐channel (carries slow outward K + ‐current, I KS ; Abbott, 2020; Chan et al, 2020) can contribute to the induction of prolonged APD (leading to further cardiac arrhythmias through long‐QT; Huang et al, 2018; Wu & Sanguinetti, 2016), in this group of investigations, we first recorded the APs under KCNQ1/KCNE1‐channel current activator (1 µM for 30 min, ML‐277) in the aged cardiomyocytes. The representative original AP traces are given in Figure 3a.…”

“…Interestingly, that loss was reversed significantly with insulin or a PKG inhibitor. It has been previously shown how KCNQ1/KCNE1 function and localization in cardiomyocytes are controlled and regulated by several intracellular signaling pathways and factors in those pathways (Abbott, 2020; Chan et al, 2020; Huang et al, 2018; Wu & Sanguinetti, 2016). In even earlier studies, it has been documented that intracellular regulation of the KCNQ1/KCNE1 complex can shorten or lengthen the cardiac APD, enabling ventricular repolarization to be in rhythm with changes in heart rate and contractility (Jespersen et al, 2005; Marx et al, 2002).…”

“…Even early findings have shown how the changes in the expression level of a slow delayed rectifier channel can contribute to AP repolarization in the human heart (Abbott, 2020; Dixit et al, 2020; Marx et al, 2002). This type of K + ‐channel has two components, such as a major pore‐forming component, KCNQ1, and a small auxiliary component, KCNE1, and carries a slow outward K + ‐current (I KS ; Abbott, 2020; Chan et al, 2020). Moreover, the important contribution of changes in these channel subunits to the induction of prolonged APD, leading to further cardiac arrhythmias (Huang et al, 2018) has been shown.…”

Editorial to the Special Issue “Electrophysiology”

“…The IC 50 value required for its inhibition of I h or delayed-rectifier K + current was estimated to be 2.1 or 6.8 µM, respectively. HNK, or its structurally similar compounds, could exercise the pharmacological actions through its perturbations on ionic currents [ 4 ].…”