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Actions of Small Molecules on Varying Type of Membrane Ion...
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Actions of Small Molecules on Varying Type of Membrane Ion Channels 2.0

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

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 5636

Special Issue Editor

Prof. Dr. Sheng-Nan Wu

E-Mail Website
Guest Editor
Department Physiology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
Interests: electrophysiology; ionic channel; cellular electrophysiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

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 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.

Prof. Dr. Sheng-Nan Wu
Guest Editor

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Published Papers (3 papers)

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Research

17 pages, 3227 KiB  
Article
Cannabidiol Modulates M-Type K+ and Hyperpolarization-Activated Cation Currents
by Yen-Chin Liu, Edmund Cheung So and Sheng-Nan Wu
Biomedicines 2023, 11(10), 2651; https://doi.org/10.3390/biomedicines11102651 - 27 Sep 2023
Cited by 3 | Viewed by 1183
Abstract
Cannabidiol (CBD) is a naturally occurring compound found in the Cannabis plant that is known for its potential therapeutic effects. However, its impact on membrane ionic currents remains a topic of debate. This study aimed to investigate how CBD modifies various types of [...] Read more.
Cannabidiol (CBD) is a naturally occurring compound found in the Cannabis plant that is known for its potential therapeutic effects. However, its impact on membrane ionic currents remains a topic of debate. This study aimed to investigate how CBD modifies various types of ionic currents in pituitary GH3 cells. Results showed that exposure to CBD led to a concentration-dependent decrease in M-type K+ currents (IK(M)), with an IC50 of 3.6 μM, and caused the quasi-steady-state activation curve of the current to shift to a more depolarized potential with no changes in the curve’s steepness. The CBD-mediated block of IK(M) was not reversed by naloxone, suggesting that it was not mediated by opioid receptors. The IK(M) elicited by pulse-train stimulation was also decreased upon exposure to CBD. The magnitude of erg-mediated K+ currents was slightly reduced by adding CBD (10 μM), while the density of voltage-gated Na+ currents elicited by a short depolarizing pulse was not affected by it. Additionally, CBD decreased the magnitude of hyperpolarization-activated cation currents (Ih) with an IC50 of 3.3 μM, and the decrease was reversed by oxaliplatin. The quasi-steady-state activation curve of Ih was shifted in the leftward direction with no changes in the slope factor of the curve. CBD also diminished the strength of voltage-dependent hysteresis on Ih elicited by upright isosceles-triangular ramp voltage. Collectively, these findings suggest that CBD’s modification of ionic currents presented herein is independent of cannabinoid or opioid receptors and may exert a significant impact on the functional activities of excitable cells occurring in vitro or in vivo. Full article
(This article belongs to the Special Issue Actions of Small Molecules on Varying Type of Membrane Ion Channels 2.0)
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19 pages, 4867 KiB  
Article
Characterization of Stimulatory Action on Voltage-Gated Na+ Currents Caused by Omecamtiv Mecarbil, Known to Be a Myosin Activator
by Chih-Yu Ting, Chia-Lung Shih, Meng-Cheng Yu, Chao-Liang Wu and Sheng-Nan Wu
Biomedicines 2023, 11(5), 1351; https://doi.org/10.3390/biomedicines11051351 - 3 May 2023
Cited by 1 | Viewed by 1509
Abstract
Omecamtiv mecarbil (OM, CK-1827452) is recognized as an activator of myosin and has been demonstrated to be beneficial for the treatment of systolic heart failure. However, the mechanisms by which this compound interacts with ionic currents in electrically excitable cells remain largely unknown. [...] Read more.
Omecamtiv mecarbil (OM, CK-1827452) is recognized as an activator of myosin and has been demonstrated to be beneficial for the treatment of systolic heart failure. However, the mechanisms by which this compound interacts with ionic currents in electrically excitable cells remain largely unknown. The objective of this study was to investigate the effects of OM on ionic currents in GH3 pituitary cells and Neuro-2a neuroblastoma cells. In GH3 cells, whole-cell current recordings showed that the addition of OM had different potencies in stimulating the transient (INa(T)) and late components (INa(L)) of the voltage-gated Na+ current (INa) with different potencies in GH3 cells. The EC50 value required to observe the stimulatory effect of this compound on INa(T) or INa(L) in GH3 cells was found to be 15.8 and 2.3 µM, respectively. Exposure to OM did not affect the current versus voltage relationship of INa(T). However, the steady-state inactivation curve of the current was observed to shift towards a depolarized potential of approximately 11 mV, with no changes in the slope factor of the curve. The addition of OM resulted in an increase in the decaying time constant during the cumulative inhibition of INa(T) in response to pulse-train depolarizing stimuli. Furthermore, the presence of OM led to a shortening of the recovery time constant in the slow inactivation of INa(T). Adding OM also resulted in an augmentation of the strength of the window Na+ current, which was evoked by a short ascending ramp voltage. However, the OM exposure had little to no effect on the magnitude of L-type Ca2+ currents in GH3 cells. On the other hand, the delayed-rectifier K+ currents in GH3 cells were observed to be mildly suppressed in its presence. Neuro-2a cells also showed a susceptibility to the differential stimulation of INa(T) or INa(L) upon the addition of OM. Molecular analysis revealed potential interactions between the OM molecule and hNaV1.7 channels. Overall, the direct stimulation of INa(T) and INa(L) by OM is assumed to not be mediated by an interaction with myosin, and this has potential implications for its pharmacological or therapeutic actions occurring in vivo. Full article
(This article belongs to the Special Issue Actions of Small Molecules on Varying Type of Membrane Ion Channels 2.0)
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20 pages, 1563 KiB  
Article
Acetylcholine Reduces L-Type Calcium Current without Major Changes in Repolarization of Canine and Human Purkinje and Ventricular Tissue
by Arie O. Verkerk, Illés J. Doszpod, Isabella Mengarelli, Tibor Magyar, Alexandra Polyák, Bence Pászti, Igor R. Efimov, Ronald Wilders and István Koncz
Biomedicines 2022, 10(11), 2987; https://doi.org/10.3390/biomedicines10112987 - 21 Nov 2022
Cited by 6 | Viewed by 2501
Abstract
Vagal nerve stimulation (VNS) holds a strong basis as a potentially effective treatment modality for chronic heart failure, which explains why a multicenter VNS study in heart failure with reduced ejection fraction is ongoing. However, more detailed information is required on the effect [...] Read more.
Vagal nerve stimulation (VNS) holds a strong basis as a potentially effective treatment modality for chronic heart failure, which explains why a multicenter VNS study in heart failure with reduced ejection fraction is ongoing. However, more detailed information is required on the effect of acetylcholine (ACh) on repolarization in Purkinje and ventricular cardiac preparations to identify the advantages, risks, and underlying cellular mechanisms of VNS. Here, we studied the effect of ACh on the action potential (AP) of canine Purkinje fibers (PFs) and several human ventricular preparations. In addition, we characterized the effects of ACh on the L-type Ca2+ current (ICaL) and AP of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and performed computer simulations to explain the observed effects. Using microelectrode recordings, we found a small but significant AP prolongation in canine PFs. In the human myocardium, ACh slightly prolonged the AP in the midmyocardium but resulted in minor AP shortening in subepicardial tissue. Perforated patch-clamp experiments on hiPSC-CMs demonstrated that 5 µM ACh caused an ≈15% decrease in ICaL density without changes in gating properties. Using dynamic clamp, we found that under blocked K+ currents, 5 µM ACh resulted in an ≈23% decrease in AP duration at 90% of repolarization in hiPSC-CMs. Computer simulations using the O’Hara–Rudy human ventricular cell model revealed that the overall effect of ACh on AP duration is a tight interplay between the ACh-induced reduction in ICaL and ACh-induced changes in K+ currents. In conclusion, ACh results in minor changes in AP repolarization and duration of canine PFs and human ventricular myocardium due to the concomitant inhibition of inward ICaL and outward K+ currents, which limits changes in net repolarizing current and thus prevents major changes in AP repolarization. Full article
(This article belongs to the Special Issue Actions of Small Molecules on Varying Type of Membrane Ion Channels 2.0)
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