Editorial

2 pages, 163 KiB

Open AccessEditorial

Editorial to the Special Issue “Electrophysiology”

by Sheng-Nan Wu and Chin-Wei Huang

Int. J. Mol. Sci. 2021, 22(6), 2956; https://doi.org/10.3390/ijms22062956 - 15 Mar 2021

Cited by 7 | Viewed by 1727

Ion channels are well recognized to select ions to pass through the cell membrane in a wide variety of cells [...] Full article

(This article belongs to the Special Issue Electrophysiology)

Research

Jump to: Editorial, Other

15 pages, 2821 KiB

Open AccessArticle

Permissive Modulation of Sphingosine-1-Phosphate-Enhanced Intracellular Calcium on BK_Ca Channel of Chromaffin Cells

by Adonis Z. Wu, Tzu-Lun Ohn, Ren-Jay Shei, Huei-Fang Wu, Yong-Cyuan Chen, Hsiang-Chun Lee, Dao-Fu Dai and Sheng-Nan Wu

Int. J. Mol. Sci. 2021, 22(4), 2175; https://doi.org/10.3390/ijms22042175 - 22 Feb 2021

Cited by 3 | Viewed by 2494

Abstract

Sphingosine-1-phosphate (S1P), is a signaling sphingolipid which acts as a bioactive lipid mediator. We assessed whether S1P had multiplex effects in regulating the large-conductance Ca²⁺-activated K⁺ channel (BK_Ca) in catecholamine-secreting chromaffin cells. Using multiple patch-clamp modes, Ca²⁺ [...] Read more.

Sphingosine-1-phosphate (S1P), is a signaling sphingolipid which acts as a bioactive lipid mediator. We assessed whether S1P had multiplex effects in regulating the large-conductance Ca²⁺-activated K⁺ channel (BK_Ca) in catecholamine-secreting chromaffin cells. Using multiple patch-clamp modes, Ca²⁺ imaging, and computational modeling, we evaluated the effects of S1P on the Ca²⁺-activated K⁺ currents (I_K(Ca)) in bovine adrenal chromaffin cells and in a pheochromocytoma cell line (PC12). In outside-out patches, the open probability of BK_Ca channel was reduced with a mean-closed time increment, but without a conductance change in response to a low-concentration S1P (1 µM). The intracellular Ca²⁺ concentration (Ca_i) was elevated in response to a high-dose (10 µM) but not low-dose of S1P. The single-channel activity of BK_Ca was also enhanced by S1P (10 µM) in the cell-attached recording of chromaffin cells. In the whole-cell voltage-clamp, a low-dose S1P (1 µM) suppressed I_K(Ca), whereas a high-dose S1P (10 µM) produced a biphasic response in the amplitude of I_K(Ca), i.e., an initial decrease followed by a sustained increase. The S1P-induced I_K(Ca) enhancement was abolished by BAPTA. Current-clamp studies showed that S1P (1 µM) increased the action potential (AP) firing. Simulation data revealed that the decreased BK_Ca conductance leads to increased AP firings in a modeling chromaffin cell. Over a similar dosage range, S1P (1 µM) inhibited I_K(Ca) and the permissive role of S1P on the BK_Ca activity was also effectively observed in the PC12 cell system. The S1P-mediated I_K(Ca) stimulation may result from the elevated Ca_i, whereas the inhibition of BK_Ca activity by S1P appears to be direct. By the differentiated tailoring BK_Ca channel function, S1P can modulate stimulus-secretion coupling in chromaffin cells. Full article

(This article belongs to the Special Issue Electrophysiology)

► Show Figures

Figure 1

30 pages, 12253 KiB

Open AccessArticle

In Silico Assessment of Class I Antiarrhythmic Drug Effects on Pitx2-Induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues

by Jieyun Bai, Yijie Zhu, Andy Lo, Meng Gao, Yaosheng Lu, Jichao Zhao and Henggui Zhang

Int. J. Mol. Sci. 2021, 22(3), 1265; https://doi.org/10.3390/ijms22031265 - 27 Jan 2021

Cited by 10 | Viewed by 3349

Abstract

Electrical remodelling as a result of homeodomain transcription factor 2 (Pitx2)-dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to class I antiarrhythmic drugs (AADs). The possible reasons behind this remain [...] Read more.

Electrical remodelling as a result of homeodomain transcription factor 2 (Pitx2)-dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of the AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action po-tential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmaco-logical effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax), and decreased AP duration (APD), conduction velocity (CV), and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that disopyramide may be more effective against Pitx2-induced AF than propafenone and quinidine by prolonging WL. Full article

(This article belongs to the Special Issue Electrophysiology)

► Show Figures

Graphical abstract

18 pages, 6515 KiB

Open AccessArticle

Effectiveness in Block by Dexmedetomidine of Hyperpolarization-Activated Cation Current, Independent of Its Agonistic Effect on α₂-Adrenergic Receptors

by Te-Ling Lu, Te-Jung Lu and Sheng-Nan Wu

Int. J. Mol. Sci. 2020, 21(23), 9110; https://doi.org/10.3390/ijms21239110 - 30 Nov 2020

Cited by 12 | Viewed by 1843

Abstract

Dexmedetomidine (DEX), a highly selective agonist of α₂-adrenergic receptors, has been tailored for sedation without risk of respiratory depression. Our hypothesis is that DEX produces any direct perturbations on ionic currents (e.g., hyperpolarization-activated cation current, I_h). In this study, [...] Read more.

Dexmedetomidine (DEX), a highly selective agonist of α₂-adrenergic receptors, has been tailored for sedation without risk of respiratory depression. Our hypothesis is that DEX produces any direct perturbations on ionic currents (e.g., hyperpolarization-activated cation current, I_h). In this study, addition of DEX to pituitary GH₃ cells caused a time- and concentration-dependent reduction in the amplitude of I_h with an IC₅₀ value of 1.21 μM and a K_D value of 1.97 μM. A hyperpolarizing shift in the activation curve of I_h by 10 mV was observed in the presence of DEX. The voltage-dependent hysteresis of I_h elicited by long-lasting triangular ramp pulse was also dose-dependently reduced during its presence. In continued presence of DEX (1 μM), further addition of OXAL (10 μM) or replacement with high K⁺ could reverse DEX-mediated inhibition of I_h, while subsequent addition of yohimbine (10 μM) did not attenuate the inhibitory effect on I_h amplitude. The addition of 3 μM DEX mildly suppressed the amplitude of erg-mediated K⁺ current. Under current-clamp potential recordings, the exposure to DEX could diminish the firing frequency of spontaneous action potentials. In pheochromocytoma PC12 cells, DEX was effective at suppressing I_h together with a slowing in activation time course of the current. Taken together, findings from this study strongly suggest that during cell exposure to DEX used at clinically relevant concentrations, the DEX-mediated block of I_h appears to be direct and would particularly be one of the ionic mechanisms underlying reduced membrane excitability in the in vivo endocrine or neuroendocrine cells. Full article

(This article belongs to the Special Issue Electrophysiology)

► Show Figures

Figure 1

18 pages, 3124 KiB

Open AccessArticle

The Specific Effects of OD-1, a Peptide Activator, on Voltage-Gated Sodium Current and Seizure Susceptibility

by Ming-Chi Lai, Sheng-Nan Wu and Chin-Wei Huang

Int. J. Mol. Sci. 2020, 21(21), 8254; https://doi.org/10.3390/ijms21218254 - 04 Nov 2020

Cited by 9 | Viewed by 1727

Abstract

OD-1, a scorpion toxin, has been previously recognized as an activator of voltage-gated Na⁺ currents. To what extent this agent can alter hippocampal neuronal Na⁺ currents and network excitability and how it can be applied to neuronal hyperexcitability research remains unclear. [...] Read more.

OD-1, a scorpion toxin, has been previously recognized as an activator of voltage-gated Na⁺ currents. To what extent this agent can alter hippocampal neuronal Na⁺ currents and network excitability and how it can be applied to neuronal hyperexcitability research remains unclear. With the aid of patch-clamp technology, it was revealed that, in mHippoE-14 hippocampal neurons, OD-1 produced a concentration-, time-, and state-dependent rise in the peak amplitude of I_Na. It shifted the I_Na inactivation curve to a less negative potential and increased the frequency of spontaneous action currents. Further characterization of neuronal excitability revealed higher excitability in the hippocampal slices treated with OD-1 as compared with the control slices. A stereotaxic intrahippocampal injection of OD-1 generated a significantly higher frequency of spontaneous seizures and epileptiform discharges compared with intraperitoneal injection of lithium-pilocarpine- or kainic acid-induced epilepsy, with comparable pathological changes. Carbamazepine significantly attenuated OD-1 induced seizures and epileptiform discharges. The OD-1-mediated modifications of I_Na altered the electrical activity of neurons in vivo and OD-1 could potentially serve as a novel seizure and excitotoxicity model. Full article

(This article belongs to the Special Issue Electrophysiology)

► Show Figures

Figure 1

17 pages, 3695 KiB

Open AccessArticle

Characterization of the Synergistic Inhibition of I_K(erg) and I_K(DR) by Ribociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor

by Pin-Yen Liu, Wei-Ting Chang and Sheng-Nan Wu

Int. J. Mol. Sci. 2020, 21(21), 8078; https://doi.org/10.3390/ijms21218078 - 29 Oct 2020

Cited by 8 | Viewed by 2239

Abstract

Ribociclib (RIB, LE011, Kisqali^®), an orally administered inhibitor of cyclin-dependent kinase-4/6 (CDK-4/6) complex, is clinically effective for the treatment of several malignancies, including advanced breast cancer. However, information regarding the effects of RIB on membrane ion currents is limited. In this [...] Read more.

Ribociclib (RIB, LE011, Kisqali^®), an orally administered inhibitor of cyclin-dependent kinase-4/6 (CDK-4/6) complex, is clinically effective for the treatment of several malignancies, including advanced breast cancer. However, information regarding the effects of RIB on membrane ion currents is limited. In this study, the addition of RIB to pituitary tumor (GH₃) cells decreased the peak amplitude of erg-mediated K⁺ current (I_K(erg)), which was accompanied by a slowed deactivation rate of the current. The IC₅₀ value for RIB-perturbed inhibition of deactivating I_K(erg) in these cells was 2.7 μM. In continued presence of μM RIB, neither the subsequent addition of 17β-estradiol (30 μM), phorbol 12-myristate 13-acetate (10 μM), or transforming growth factor-β (1 μM) counteracted the inhibition of deactivating I_K(erg). Its presence affected the decrease in the degree of voltage-dependent hysteresis for I_K(erg) elicitation by long-duration triangular ramp voltage commands. The presence of RIB differentially inhibited the peak or sustained component of delayed rectifier K⁺ current (I_K(DR)) with an effective IC₅₀ of 28.7 or 11.4 μM, respectively, while it concentration-dependently decreased the amplitude of M-type K⁺ current with IC₅₀ of 13.3 μM. Upon 10-s long membrane depolarization, RIB elicited a decrease in the I_K(DR) amplitude, which was concomitant with an accelerated inactivation time course. However, the inability of RIB (10 μM) to modify the magnitude of the hyperpolarization-activated cation current was disclosed. The mean current–voltage relationship of I_K(erg) present in HL-1 atrial cardiomyocytes was inhibited in the presence of RIB (10 μM). Collectively, the hyperpolarization-activated cation current was observed. RIB-mediated perturbations in ionic currents presented herein are upstream of its suppressive action on cytosolic CDK-4/6 activities and partly participates in its modulatory effects on the functional activities of pituitary tumor cells (e.g., GH₃ cells) or cardiac myocytes (e.g., HL-1 cells). Full article

(This article belongs to the Special Issue Electrophysiology)

► Show Figures

Graphical abstract

16 pages, 3407 KiB

Open AccessArticle

Nicotinamide Phosphoribosyltransferase (Nampt)/Nicotinamide Adenine Dinucleotide (NAD) Axis Suppresses Atrial Fibrillation by Modulating the Calcium Handling Pathway

by Duo Feng, DongZhu Xu, Nobuyuki Murakoshi, Kazuko Tajiri, Rujie Qin, Saori Yonebayashi, Yuta Okabe, Siqi Li, Zixun Yuan, Kazutaka Aonuma and Masaki Ieda

Int. J. Mol. Sci. 2020, 21(13), 4655; https://doi.org/10.3390/ijms21134655 - 30 Jun 2020

Cited by 8 | Viewed by 3513 | Correction

Abstract

Aging and obesity are the most prominent risk factors for onset of atrial fibrillation (AF). Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme that catalyzes nicotinamide adenine dinucleotide (NAD) activity. Nampt and NAD are essential for maintenance of cellular redox homeostasis and modulation of [...] Read more.

Aging and obesity are the most prominent risk factors for onset of atrial fibrillation (AF). Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme that catalyzes nicotinamide adenine dinucleotide (NAD) activity. Nampt and NAD are essential for maintenance of cellular redox homeostasis and modulation of cellular metabolism, and their expression levels decrease with aging and obesity. However, a role for Nampt in AF is unknown. The present study aims to test whether there is a role of Nampt/NAD axis in the pathogenesis of obesity-induced AF. Male C57BL/6J (WT) mice and heterozygous Nampt knockout (NKO) mice were fed with a normal chow diet (ND) or a high-fat diet (HFD). Electrophysiological study showed that AF inducibility was significantly increased in WT+HFD, NKO+ND, and NKO+HFD mice compared with WT+ND mice. AF duration was significantly longer in WT+HFD and NKO+ND mice and further prolonged in NKO+HFD mice compared with WT+ND mice and the calcium handling pathway was altered on molecular level. Also, treatment with nicotinamide riboside, a NAD precursor, partially restored the HFD-induced AF perpetuation. Overall, this work demonstrates that partially deletion of Nampt facilitated HFD-induced AF through increased diastolic calcium leaks. The Nampt/NAD axis may be a potent therapeutic target for AF. Full article

(This article belongs to the Special Issue Electrophysiology)

► Show Figures

Graphical abstract

22 pages, 7531 KiB

Open AccessArticle

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

by Ming-Huan Chan, Hwei-Hsien Chen, Yi-Ching Lo and Sheng-Nan Wu

Int. J. Mol. Sci. 2020, 21(12), 4260; https://doi.org/10.3390/ijms21124260 - 15 Jun 2020

Cited by 8 | Viewed by 2129

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 [...] Read more.

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 (I_h) 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 I_h 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 I_h density elicited by long-lasting triangular ramp pulse was attenuated by the presence of HNK. The HNK addition also diminished the magnitude of deactivating I_h density elicited by ramp-up depolarization with varying durations. The effective half-maximal concentration (IC₅₀) value needed to inhibit the density of I_h 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 I_h 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. Full article

(This article belongs to the Special Issue Electrophysiology)

► Show Figures

Figure 1

23 pages, 4712 KiB

Open AccessArticle

Inhibitory Effective Perturbations of Cilobradine (DK-AH269), A Blocker of HCN Channels, on the Amplitude and Gating of Both Hyperpolarization-Activated Cation and Delayed-Rectifier Potassium Currents

by Te-Ling Lu, Te-Jung Lu and Sheng-Nan Wu

Int. J. Mol. Sci. 2020, 21(7), 2416; https://doi.org/10.3390/ijms21072416 - 31 Mar 2020

Cited by 12 | Viewed by 2570

Abstract

Cilobradine (CIL, DK-AH269), an inhibitor of hyperpolarization-activated cation current (I_h), has been observed to possess pro-arrhythmic properties. Whether and how CIL is capable of perturbing different types of membrane ionic currents existing in electrically excitable cells, however, is incompletely understood. [...] Read more.

Cilobradine (CIL, DK-AH269), an inhibitor of hyperpolarization-activated cation current (I_h), has been observed to possess pro-arrhythmic properties. Whether and how CIL is capable of perturbing different types of membrane ionic currents existing in electrically excitable cells, however, is incompletely understood. In this study, we intended to examine possible modifications by it or other structurally similar compounds of ionic currents in pituitary tumor (GH₃) cells and in heart-derived H9c2 cells. The standard whole-cell voltage-clamp technique was performed to examine the effect of CIL on ionic currents. GH₃-cell exposure to CIL suppressed the density of hyperpolarization-evoked I_h in a concentration-dependent manner with an effective IC₅₀ of 3.38 μM. Apart from its increase in the activation time constant of I_h during long-lasting hyperpolarization, the presence of CIL (3 μM) distinctly shifted the steady-state activation curve of I_h triggered by a 2-s conditioning pulse to a hyperpolarizing direction by 10 mV. As the impedance-frequency relation of I_h was studied, its presence raised the impedance magnitude at the resonance frequency induced by chirp voltage. CIL also suppressed delayed-rectifier K⁺ current (I_K(DR)) followed by the accelerated inactivation time course of this current, with effective IC₅₀ (measured at late I_K(DR)) or K_D value of 3.54 or 3.77 μM, respectively. As the CIL concentration increased 1 to 3 μM, the inactivation curve of I_K(DR) elicited by 1- or 10-s conditioning pulses was shifted to a hyperpolarizing potential by approximately 10 mV, and the recovery of I_K(DR) inactivation during its presence was prolonged. The peak Na⁺ current (I_Na) during brief depolarization was resistant to being sensitive to the presence of CIL, yet to be either decreased by subsequent addition of A-803467 or enhanced by that of tefluthrin. In cardiac H9c2 cells, unlike the CIL effect, the addition of either ivabradine or zatebradine mildly led to a lowering in I_K(DR) amplitude with no conceivable change in the inactivation time course of the current. Taken together, the compound like CIL, which was tailored to block hyperpolarization-activated cation (HCN) channels effectively, was also capable of altering the amplitude and gating of I_K(DR), thereby influencing the functional activities of electrically excitable cells, such as GH₃ cells. Full article

(This article belongs to the Special Issue Electrophysiology)

► Show Figures

Figure 1

13 pages, 2202 KiB

Open AccessArticle

Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes

by Wei-Ting Chang, Ping-Yen Liu, Kaisen Lee, Yin-Hsun Feng and Sheng-Nan Wu

Int. J. Mol. Sci. 2020, 21(5), 1672; https://doi.org/10.3390/ijms21051672 - 29 Feb 2020

Cited by 6 | Viewed by 2408

Abstract

Lapatinib (LAP) and sorafenib (SOR) are multitargeted tyrosine kinase inhibitors (TKIs) with antineoplastic properties. In clinical observations, LAP and SOR may contribute to QTc prolongation, but the detailed mechanism for this has been largely unexplored. In this study, we investigated whether LAP and [...] Read more.

Lapatinib (LAP) and sorafenib (SOR) are multitargeted tyrosine kinase inhibitors (TKIs) with antineoplastic properties. In clinical observations, LAP and SOR may contribute to QTc prolongation, but the detailed mechanism for this has been largely unexplored. In this study, we investigated whether LAP and SOR affect the activities of membrane ion channels. Using a small animal model and primary cardiomyocytes, we studied the impact of LAP and SOR on Na⁺ and K⁺ currents. We found that LAP-induced QTc prolongation in mice was reversed by isoproterenol. LAP or SOR suppressed the amplitude of the slowly activating delayed-rectifier K⁺ current (I_K(S)) in H9c2 cells in a time- and concentration-dependent fashion. The LAP-mediated inhibition of I_K(S) was reversed by adding isoproterenol or meclofenamic acid, but not by adding diazoxide. The steady-state activation curve of I_K(S) during exposure to LAP or SOR was shifted toward a less negative potential, with no change in the gating charge required to activate the current. LAP shortened the recovery from I_K(S) deactivation. As rapid repetitive stimuli, the I_K(S) amplitude decreased; however; the LAP-induced inhibition of I_K(S) remained effective. LAP or SOR alone also suppressed inwardly rectifying K⁺ and voltage-gated Na⁺ current in neonatal rat ventricular myocytes. The inhibition of ionic currents during exposure to TKIs could be an important mechanism underlying changes in QTc intervals. Full article

(This article belongs to the Special Issue Electrophysiology)

► Show Figures

Figure 1

20 pages, 3629 KiB

Open AccessArticle

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

by Hung-Te Hsu, Yi-Ching Lo and Sheng-Nan Wu

Int. J. Mol. Sci. 2020, 21(4), 1441; https://doi.org/10.3390/ijms21041441 - 20 Feb 2020

Cited by 14 | Viewed by 2261

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 (I_K(erg) [...] Read more.

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 (I_K(erg)) together with an increased deactivation rate of the current in pituitary GH₃ cells. The IC₅₀ and K_D values of UCL-2077-induced inhibition of I_K(erg) were 4.7 and 5.1 μM, respectively. UCL-2077 (10 μM) distinctly shifted the midpoint in the activation curve of I_K(erg) to less hyperpolarizing potentials by 17 mV. Its presence decreased the degree of voltage hysteresis for I_K(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. Full article

(This article belongs to the Special Issue Electrophysiology)

► Show Figures

Figure 1

16 pages, 5234 KiB

Open AccessArticle

Characterization of Inhibitory Effectiveness in Hyperpolarization-Activated Cation Currents by a Group of ent-Kaurane-Type Diterpenoids from Croton tonkinensis

by Ping-Chung Kuo, Yen-Chin Liu, Yi-Ching Lo and Sheng-Nan Wu

Int. J. Mol. Sci. 2020, 21(4), 1268; https://doi.org/10.3390/ijms21041268 - 13 Feb 2020

Cited by 5 | Viewed by 2519

Abstract

Croton is an extensive flowering plant genus in the spurge family, Euphorbiaceae. Three croton compounds with the common ent-kaurane skeleton have been purified from Croton tonkinensis. Methods: We examined any modifications of croton components (i.e., croton-01 [ent-18-acetoxy-7α-hydroxykaur-16-en-15-one], croton-02 [ [...] Read more.

Croton is an extensive flowering plant genus in the spurge family, Euphorbiaceae. Three croton compounds with the common ent-kaurane skeleton have been purified from Croton tonkinensis. Methods: We examined any modifications of croton components (i.e., croton-01 [ent-18-acetoxy-7α-hydroxykaur-16-en-15-one], croton-02 [ent-7α,14β-dihydroxykaur-16-en-15-one] and croton-03 [ent-1β-acetoxy-7α,14β-dihydroxykaur-16-en-15-one] on either hyperpolarization-activated cation current (I_h) or erg-mediated K⁺ current identified in pituitary tumor (GH₃) cells and in rat insulin-secreting (INS-1) cells via patch-clamp methods. Results: Addition of croton-01, croton-02, or croton-03 effectively and differentially depressed I_h amplitude. Croton-03 (3 μM) shifted the activation curve of I_h to a more negative potential by approximately 11 mV. The voltage-dependent hysteresis of I_h was also diminished by croton-03 administration. Croton-03-induced depression of I_h could not be attenuated by SQ-22536 (10 μM), an inhibitor of adenylate cyclase, but indeed reversed by oxaliplatin (10 μM). The I_h in INS-1 cells was also depressed effectively by croton-03. Conclusion: Our study highlights the evidence that these ent-kaurane diterpenoids might conceivably perturb these ionic currents through which they have high influence on the functional activities of endocrine or neuroendocrine cells. Full article

(This article belongs to the Special Issue Electrophysiology)

► Show Figures

Figure 1

17 pages, 7026 KiB

Open AccessArticle

Characterization in Dual Activation by Oxaliplatin, a Platinum-Based Chemotherapeutic Agent of Hyperpolarization-Activated Cation and Electroporation-Induced Currents

by Wei-Ting Chang, Zi-Han Gao, Shih-Wei Li, Ping-Yen Liu, Yi-Ching Lo and Sheng-Nan Wu

Int. J. Mol. Sci. 2020, 21(2), 396; https://doi.org/10.3390/ijms21020396 - 08 Jan 2020

Cited by 12 | Viewed by 2477

Abstract

Oxaliplatin (OXAL) is regarded as a platinum-based anti-neoplastic agent. However, its perturbations on membrane ionic currents in neurons and neuroendocrine or endocrine cells are largely unclear, though peripheral neuropathy has been noted during its long-term administration. In this study, we investigated how the [...] Read more.

Oxaliplatin (OXAL) is regarded as a platinum-based anti-neoplastic agent. However, its perturbations on membrane ionic currents in neurons and neuroendocrine or endocrine cells are largely unclear, though peripheral neuropathy has been noted during its long-term administration. In this study, we investigated how the presence of OXAL and other related compounds can interact with two types of inward currents; namely, hyperpolarization-activated cation current (I_h) and membrane electroporation-induced current (I_MEP). OXAL increased the amplitude or activation rate constant of I_h in a concentration-dependent manner with effective EC₅₀ or K_D values of 3.2 or 6.4 μM, respectively, in pituitary GH₃ cells. The stimulation by this agent of I_h could be attenuated by subsequent addition of ivabradine, protopine, or dexmedetomidine. Cell exposure to OXAL (3 μM) resulted in an approximately 11 mV rightward shift in I_h activation along the voltage axis with minimal changes in the gating charge of the curve. The exposure to OXAL also effected an elevation in area of the voltage-dependent hysteresis elicited by long-lasting triangular ramp. Additionally, its application resulted in an increase in the amplitude of I_MEP elicited by large hyperpolarization in GH₃ cells with an EC₅₀ value of 1.3 μM. However, in the continued presence of OXAL, further addition of ivabradine, protopine, or dexmedetomidine always resulted in failure to attenuate the OXAL-induced increase of I_MEP amplitude effectively. Averaged current-voltage relation of membrane electroporation-induced current (I_MEP) was altered in the presence of OXAL. In pituitary R1220 cells, OXAL-stimulated I_h remained effective. In Rolf B1.T olfactory sensory neurons, this agent was also observed to increase I_MEP in a concentration-dependent manner. In light of the findings from this study, OXAL-mediated increases of I_h and I_MEP may coincide and then synergistically act to increase the amplitude of inward currents, raising the membrane excitability of electrically excitable cells, if similar in vivo findings occur. Full article

(This article belongs to the Special Issue Electrophysiology)

► Show Figures

Figure 1

Other

Jump to: Editorial, Research

2 pages, 750 KiB

Open AccessCorrection

Correction: Feng et al. Nicotinamide Phosphoribosyltransferase (Nampt)/Nicotinamide Adenine Dinucleotide (NAD) Axis Suppresses Atrial Fibrillation by Modulating the Calcium Handling Pathway. Int. J. Mol. Sci. 2020, 21, 4655

by Duo Feng, DongZhu Xu, Nobuyuki Murakoshi, Kazuko Tajiri, Rujie Qin, Saori Yonebayashi, Yuta Okabe, Siqi Li, Zixun Yuan, Kazutaka Aonuma and Masaki Ieda

Int. J. Mol. Sci. 2021, 22(19), 10881; https://doi.org/10.3390/ijms221910881 - 08 Oct 2021

Viewed by 1448

Abstract

The authors wish to make the following corrections to this paper [...] Full article

(This article belongs to the Special Issue Electrophysiology)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Electrophysiology

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (14 papers)

Editorial

Research

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI