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Actions of Small Molecules on Varying Type of Membrane Ion Channels

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (15 August 2022) | Viewed by 15451

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Prof. Dr. Sheng-Nan Wu

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National Cheng Kung University Medical College, Tainan, Taiwan
Interests: electrophysiology; ionic channel; cellular electrophysiology
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Dear Colleagues,

Ion channels, viewed as enigmatic proteins, are recognized to select ions to pass through the cell membrane in a wide variety of cells. Changes in these various types of ion channels can act to perturb the functional activities of Na⁺, Ca²⁺, and K⁺ channels, and therefore play essential roles in numerous fundamental physiological functions, such as controlling membrane excitability, generating and shaping action potentials, regulating cell volume, and regulating epithelial secretion. Recent progress in the biophysical or pharmacological characterization of ion channels potentially modified by different small molecules (i.e., ion channel modulators) has demonstrated the fundamental importance of ion channels in physiology, pathophysiology, pharmacology, and various pathologic disorders. However, the potential of these small-molecule modulators as targets for novel and efficacious therapeutics is still incompletely understood. It is hoped that this Special Issue in Biomedicines will provide the current understanding of several intriguing small molecules which can effectively perturb the amplitude, gating kinetics, and voltage-dependent hysteresis of membrane ionic currents, such as voltage-gated Na⁺ current, hyperpolarization-activated cation current, M-type K⁺ current, or erg-mediated K⁺ current.

Dr. Sheng-Nan Wu
Guest Editor

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Research

19 pages, 2630 KiB

Open AccessArticle

Inhibitory Effectiveness in Delayed-Rectifier Potassium Current Caused by Vortioxetine, Known to Be a Novel Antidepressant

by Hung-Tsung Hsiao, Jeffrey Chi-Fei Wang and Sheng-Nan Wu

Biomedicines 2022, 10(6), 1318; https://doi.org/10.3390/biomedicines10061318 - 03 Jun 2022

Cited by 2 | Viewed by 1474

Abstract

Vortioxetine (VOR) is recognized to exert antidepressant actions. However, whether this drug modifies ionic currents in excitable cells remains unclear. The aim of this study was to explore the electrophysiological effects of VOR and other related compounds in pituitary GH₃ cells and in Neuro-2a cells. VOR suppressed the delayed-rectifier K⁺ current (I_K(DR)) in a concentration-, time-, and state-dependent manner. Effective IC₅₀ values needed to inhibit peak and sustained I_K(DR) were computed to be 31.2 and 8.5 μM, respectively, while the K_D value estimated from minimal binding scheme was 7.9 μM. Cell exposure to serotonin (10 μM) alone failed to alter I_K(DR), while fluoxetine (10 μM), a compound structurally similar to VOR, mildly suppressed current amplitude. In continued presence of VOR, neither further addition of propranolol nor risperidone reversed VOR-mediated inhibition of I_K(DR). Increasing VOR concentration not only depressed I_K(DR) conductance but also shifted toward the hyperpolarized potential. As the VOR concentration was raised, the recovery of I_K(DR) block became slowed. The I_K(DR) activated by a downsloping ramp was suppressed by its presence. The inhibition of I_K(DR) by a train pulse was enhanced during exposure to VOR. In Neuro-2a cells, this drug decreased I_K(DR). Overall, inhibitory effects of VOR on ionic currents might constitute another underlying mechanism of its actions. Full article

(This article belongs to the Special Issue Actions of Small Molecules on Varying Type of Membrane Ion Channels)

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22 pages, 3902 KiB

Open AccessArticle

The Effectiveness of Isoplumbagin and Plumbagin in Regulating Amplitude, Gating Kinetics, and Voltage-Dependent Hysteresis of erg-mediated K⁺ Currents

by Linyi Chen, Hsin-Yen Cho, Tzu-Hsien Chuang, Ting-Ling Ke and Sheng-Nan Wu

Biomedicines 2022, 10(4), 780; https://doi.org/10.3390/biomedicines10040780 - 27 Mar 2022

Cited by 5 | Viewed by 1821

Abstract

Isoplumbagin (isoPLB, 5-hydroxy-3-methyl-1,4-naphthoquinone), a naturally occurring quinone, has been observed to exercise anti-inflammatory, antimicrobial, and antineoplastic activities. Notably, whether and how isoPLB, plumbagin (PLB), or other related compounds impact transmembrane ionic currents is not entirely clear. In this study, during GH₃-cell exposure to isoPLB, the peak and sustained components of an erg (ether-à-go-go related gene)-mediated K⁺ current (I_K(erg)) evoked with long-lasting-step hyperpolarization were concentration-dependently decreased, with a concomitant increase in the decaying time constant of the deactivating current. The presence of isoPLB led to a differential reduction in the peak and sustained components of deactivating I_K(erg) with effective IC₅₀ values of 18.3 and 2.4 μM, respectively, while the K_D value according to the minimum binding scheme was estimated to be 2.58 μM. Inhibition by isoPLB of I_K(erg) was not reversed by diazoxide; however, further addition of isoPLB, during the continued exposure to 4,4′-dithiopyridine, did not suppress I_K(erg) further. The recovery of I_K(erg) by a two-step voltage pulse with a geometric progression was slowed in the presence of isoPLB, and the decaying rate of I_K(erg) activated by the envelope-of-tail method was increased in its presence. The strength of the I_K(erg) hysteresis in response to an inverted isosceles-triangular ramp pulse was diminished by adding isoPLB. A mild inhibition of the delayed-rectifier K⁺ current (I_K(DR)) produced by the presence of isoPLB was seen in GH₃ cells, while minimal changes in the magnitude of the voltage-gated Na⁺ current were demonstrated in its presence. Moreover, the I_K(erg) identified in MA-10 Leydig tumor cells was blocked by adding isoPLB. Therefore, the effects of isoPLB or PLB on ionic currents (e.g., I_K(erg) and I_K(DR)) demonstrated herein would be upstream of our previously reported perturbations on mitochondrial morphogenesis or respiration. Taken together, the perturbations of ionic currents by isoPLB or PLB demonstrated herein are likely to contribute to the underlying mechanism through which they, or other structurally similar compounds, result in adjustments in the functional activities of different neoplastic cells (e.g., GH₃ and MA-10 cells), presuming that similar in vivo observations occur. Full article

(This article belongs to the Special Issue Actions of Small Molecules on Varying Type of Membrane Ion Channels)

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20 pages, 6444 KiB

Open AccessArticle

Activation of Voltage-Gated Na⁺ Current by GV-58, a Known Activator of Ca_V Channels

by Hsin-Yen Cho, Pei-Chun Chen, Tzu-Hsien Chuang, Meng-Cheng Yu and Sheng-Nan Wu

Biomedicines 2022, 10(3), 721; https://doi.org/10.3390/biomedicines10030721 - 20 Mar 2022

Cited by 4 | Viewed by 1676

Abstract

GV-58 ((2R)-2-[(6-{[(5-methylthiophen-2-yl)methyl]amino}-9-propyl-9H-purin-2-yl)amino]butan-1-ol) is recognized to be an activator of N- and P/Q-type Ca²⁺ currents. However, its modulatory actions on other types of ionic currents in electrically excitable cells remain largely unanswered. This study was undertaken to explore the possible modifications caused by GV-58 in ionic currents (e.g., voltage-gated Na⁺ current [I_Na], A-type K⁺ current [I_K(A)], and erg-mediated K⁺ current [I_K(erg)]) identified from pituitary GH₃ lactotrophs. GH₃ cell exposure to GV-58 enhanced the transient and late components of I_Na with varying potencies; consequently, the EC₅₀ values of GV-58 required for its differential increase in peak and late I_Na in GH₃ cells were estimated to be 8.9 and 2.6 μM, respectively. The I_Na in response to brief depolarizing pulse was respectively stimulated or suppressed by GV-58 or tetrodotoxin, but it failed to be altered by ω-conotoxin MVIID. Cell exposure to this compound increased the recovery of I_Na inactivation evoked by two-pulse protocol based on a geometrics progression; however, in its presence, there was a slowing in the inactivation rate of current decay evoked by a train of depolarizing pulses. The existence of GV-58 also resulted in an increase in the amplitude of ramp-induced resurgent and window I_Na. The presence of this compound inhibited I_K(A) magnitude, accompanied by a shortening in inactivation time course of the current; however, it mildly decreased I_K(erg). Under current-clamp conditions, GV-58 increased the frequency of spontaneous action potentials in GH₃ cells. Moreover, in NSC-34 motor neuron-like cells, the presence of GV-58 not only raised I_Na amplitude but also reduced current inactivation. Taken together, the overall work provides a noticeable yet unidentified finding which implies that, in addition to its agonistic effect on Ca²⁺ currents, GV-58 may concertedly modify the amplitude and gating kinetics of I_Na in electrically excitable cells, hence modifiying functional activities in these cells. Full article

(This article belongs to the Special Issue Actions of Small Molecules on Varying Type of Membrane Ion Channels)

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15 pages, 4499 KiB

Open AccessArticle

Zika M—A Potential Viroporin: Mutational Study and Drug Repurposing

by Prabhat Pratap Singh Tomar, Miriam Krugliak, Anamika Singh and Isaiah T. Arkin

Biomedicines 2022, 10(3), 641; https://doi.org/10.3390/biomedicines10030641 - 10 Mar 2022

Cited by 5 | Viewed by 2229

Abstract

Genus Flavivirus contains several important human pathogens. Among these, the Zika virus is an emerging etiological agent that merits concern. One of its structural proteins, prM, plays an essential role in viral maturation and assembly, making it an attractive drug and vaccine development target. Herein, we have characterized ZikV-M as a potential viroporin candidate using three different bacteria-based assays. These assays were subsequently employed to screen a library of repurposed drugs from which ten compounds were identified as ZikV-M blockers. Mutational analyses of conserved amino acids in the transmembrane domain of other flaviviruses, including West Nile and Dengue virus, were performed to study their role in ion channel activity. In conclusion, our data show that ZikV-M is a potential ion channel that can be used as a drug target for high throughput screening and drug repurposing. Full article

(This article belongs to the Special Issue Actions of Small Molecules on Varying Type of Membrane Ion Channels)

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20 pages, 2519 KiB

Open AccessArticle

The Evidence for Sparsentan-Mediated Inhibition of I_Na and I_K(erg): Possibly Unlinked to Its Antagonism of Angiotensin II or Endothelin Type a Receptor

by Tzu-Hsien Chuang, Hsin-Yen Cho and Sheng-Nan Wu

Biomedicines 2022, 10(1), 86; https://doi.org/10.3390/biomedicines10010086 - 31 Dec 2021

Cited by 10 | Viewed by 2120

Abstract

Sparsentan is viewed as a dual antagonist of endothelin type A (ET_A) receptor and angiotensin II (AngII) receptor and it could be beneficial in patients with focal segmental glomerulosclerosis. Moreover, it could improve glomerular filtration rate and augment protective tissue remodeling in mouse models of focal segmental glomerulosclerosis. The ionic mechanisms through which it interacts with the magnitude and/or gating kinetics of ionic currents in excitable cells were not thoroughly investigated. Herein, we aimed to examine the effects of varying sparsentan concentrations on ionic currents residing in pituitary GH₃ somatolactotrophs. From whole-cell current recordings made in GH₃ cells, sparsentan (0.3–100 μM) differentially inhibited the peak and late components of voltage-gated Na⁺ current (I_Na). The IC₅₀ value of sparsentan required to exert a reduction in peak and late I_Na in GH₃ cells was 15.04 and 1.21 μM, respectively; meanwhile, the K_D value estimated from its shortening in the slow component of I_Na inactivation time constant was 2.09 μM. The sparsentan (10 μM) presence did not change the overall current–voltage relationship of I_Na; however, the steady-state inactivation curve of the current was shifted to more negative potential in its presence (10 μM), with no change in the gating charge of the curve. The window I_Na activated by a brief upsloping ramp was decreased during exposure to sparsentan (10 μM); moreover, recovery of peak I_Na became slowed in its presence. The Tefluthrin (Tef)-stimulated resurgent I_Na activated in response to abrupt depolarization followed by the descending ramp pulse was additionally attenuated by subsequent application of sparsentan. In continued presence of Tef (3 μM) or β-pompilidotoxin (3 μM), further application of sparsentan (3 μM) reversed their stimulation of I_Na. However, sparsentan-induced inhibition of I_Na failed to be overcome by subsequent application of either endothelin 1 (1 μM) or angiotensin II (1 μM); moreover, in continued presence of endothelin (1 μM) or angiotensin II (1 μM), further addition of sparsentan (3 μM) effectively decreased peak I_Na. Additionally, the application of sparsentan (3 μM) inhibited the peak and late components of erg-mediated K⁺ current in GH₃ cells, although it mildly decreased the amplitude of delayed-rectifier K⁺ current. Altogether, this study provides a distinct yet unidentified finding that sparsentan may perturb the amplitude or gating of varying ionic currents in excitable cells. Full article

(This article belongs to the Special Issue Actions of Small Molecules on Varying Type of Membrane Ion Channels)

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17 pages, 2327 KiB

Open AccessArticle

Effective Perturbations on the Amplitude and Hysteresis of Erg-Mediated Potassium Current Caused by 1-Octylnonyl 8-[(2-hydroxyethyl)[6-oxo-6(undecyloxy)hexyl]amino]-octanoate (SM-102), a Cationic Lipid

by Hsin-Yen Cho, Tzu-Hsien Chuang and Sheng-Nan Wu

Biomedicines 2021, 9(10), 1367; https://doi.org/10.3390/biomedicines9101367 - 01 Oct 2021

Cited by 13 | Viewed by 5079

Abstract

SM-102 (1-octylnonyl 8-[(2-hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino]-octanoate) is an amino cationic lipid that has been tailored for the formation of lipid nanoparticles and it is one of the essential ingredients present in the Moderna^TM COVID-19 vaccine. However, to what extent it may modify varying types of plasmalemmal ionic currents remains largely uncertain. In this study, we investigate the effects of SM-102 on ionic currents either in two types of endocrine cells (e.g., rat pituitary tumor (GH₃) cells and mouse Leydig tumor (MA-10) cells) or in microglial (BV2) cells. Hyperpolarization-activated K⁺ currents in these cells bathed in high-K⁺, Ca²⁺-free extracellular solution were examined to assess the effects of SM-102 on the amplitude and hysteresis of the erg-mediated K⁺ current (I_K(erg)). The SM-102 addition was effective at blocking I_K(erg) in a concentration-dependent fashion with a half-maximal concentration (IC₅₀) of 108 μM, a value which is similar to the K_D value (i.e., 134 μM) required for its accentuation of deactivation time constant of the current. The hysteretic strength of I_K(erg) in response to the long-lasting isosceles-triangular ramp pulse was effectively decreased in the presence of SM-102. Cell exposure to TurboFectin^TM 8.0 (0.1%, v/v), a transfection reagent, was able to inhibit hyperpolarization-activated I_K(erg) effectively with an increase in the deactivation time course of the current. Additionally, in GH₃ cells dialyzed with spermine (30 μM), the I_K(erg) amplitude progressively decreased; moreover, a further bath application of SM-102 (100 μM) or TurboFectin (0.1%) diminished the current magnitude further. In MA-10 Leydig cells, the I_K(erg) was also blocked by the presence of SM-102 or TurboFectin. The IC₅₀ value for SM-102-induced inhibition of I_K(erg) in MA-10 cells was 98 μM. In BV2 microglial cells, the amplitude of the inwardly rectifying K⁺ current was inhibited by SM-102. Taken together, the presence of SM-102 concentration-dependently inhibited I_K(erg) in endocrine cells (e.g., GH₃ or MA-10 cells), and such action may contribute to their functional activities, assuming that similar in vivo findings exist. Full article

(This article belongs to the Special Issue Actions of Small Molecules on Varying Type of Membrane Ion Channels)

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