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Regulatory Mechanisms of Ion Channels and Their Potential as Therapeutic Targets 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 February 2025 | Viewed by 9307

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Prof. Dr. Joohyun Nam

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Department of Physiology, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea
Interests: cell physiology; electrophysiology; ion channel
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Dear Colleagues,

Ion channels play essential roles in both the generation of cell membrane potential and the maintenance of our organs’ overall physiological functions, such as action potential generation, electrolyte secretion, muscle contraction, and intracellular signaling. Specific channels, which exist for various ions (e.g., Ca²⁺, K⁺, Na⁺, and Cl⁻), are responsible for unique cellular functions. However, even though the development of the patch clamp technique in the 1980s dramatically advanced the identification of molecular ion channel mechanisms, the biophysical and molecular functions of many areas remain to be fully elucidated.

In addition, the dysfunction of these ion channels can play important roles in disease development and/or treatment. Hence, the identification of ion channel regulatory mechanisms, and the development of therapeutic drugs that target them, is of particular interest.

Accordingly, this paper aims to discuss research of molecular mechanisms underlying various ion channels, as well as the effects of novel drug candidates that target them.

Prof. Dr. Joohyun Nam
Guest Editor

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Keywords

ion channels
membrane proteins
molecular mechanisms
therapeutic targets

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Published Papers (5 papers)

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Research

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22 pages, 4128 KiB

Open AccessArticle

Examination of the Effect of Dimethyl Trisulfide in Acute Stress Mouse Model with the Potential Involvement of the TRPA1 Ion Channel

by Kitti Göntér, Ágnes Dombi, Viktória Kormos, Erika Pintér and Gábor Pozsgai

Int. J. Mol. Sci. 2024, 25(14), 7701; https://doi.org/10.3390/ijms25147701 - 13 Jul 2024

Viewed by 1094

Abstract

Polysulfides are endogenously produced in mammals and generally associated with protective functions. Our aim was to investigate the effect of dimethyl trisulfide (DMTS) in a mouse model of acute stress. DMTS activates transient receptor potential ankyrin 1 (TRPA1) channels and leads to neuropeptide release, potentially that of substance P (SP). We hypothesize that DMTS might inhibit the degrading enzymes of endocannabinoids, so this system was also investigated as another possible pathway for mediating the effects of DMTS. Trpa1 gene wild-type (WT) and knockout (KO) mice were used to confirm the role of the TRPA1 ion channel in mediating the effects of DMTS. C57BL/6J, NK1 gene KO, and Tac1 gene KO mice were used to evaluate the effect of DMTS on the release and expression of SP. Some C57BL/6J animals were treated with AM251, an inhibitor of the cannabinoid CB1 receptor, to elucidate the role of the endocannabinoid system in these processes. Open field test (OFT) and forced swim test (FST) were performed in each mouse strain. A tail suspension test (TST) was performed in Trpa1 WT and KO animals. C-FOS immunohistochemistry was carried out on Trpa1 WT and KO animals. The DMTS treatment increased the number of highly active periods and decreased immobility time in the FST in WT animals, but had no effect on the Trpa1 KO mice. The DMTS administration induced neuronal activation in the Trpa1 WT mice in the stress-related brain areas, such as the locus coeruleus, dorsal raphe nucleus, lateral septum, paraventricular nucleus of the thalamus, and paraventricular nucleus of the hypothalamus. DMTS may have a potential role in the regulation of stress-related processes, and the TRPA1 ion channel may also be involved in mediating the effects of DMTS. DMTS can be an ideal candidate for further study as a potential remedy for stress-related disorders. Full article

(This article belongs to the Special Issue Regulatory Mechanisms of Ion Channels and Their Potential as Therapeutic Targets 2.0)

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18 pages, 4018 KiB

Open AccessArticle

Novel Scorpion Toxin ω-Buthitoxin-Hf1a Selectively Inhibits Calcium Influx via Ca_V3.3 and Ca_V3.2 and Alleviates Allodynia in a Mouse Model of Acute Postsurgical Pain

by Dan Wang, Volker Herzig, Zoltan Dekan, K. Johan Rosengren, Colton D. Payne, Md. Mahadhi Hasan, Jiajie Zhuang, Emmanuel Bourinet, Lotten Ragnarsson, Paul F. Alewood and Richard J. Lewis

Int. J. Mol. Sci. 2024, 25(9), 4745; https://doi.org/10.3390/ijms25094745 - 26 Apr 2024

Viewed by 1390

Abstract

Venom peptides have evolved to target a wide range of membrane proteins through diverse mechanisms of action and structures, providing promising therapeutic leads for diseases, including pain, epilepsy, and cancer, as well as unique probes of ion channel structure-function. In this work, a high-throughput FLIPR window current screening assay on T-type Ca_V3.2 guided the isolation of a novel peptide named ω-Buthitoxin-Hf1a from scorpion Hottentotta franzwerneri crude venom. At only 10 amino acid residues with one disulfide bond, it is not only the smallest venom peptide known to target T-type Ca_Vs but also the smallest structured scorpion venom peptide yet discovered. Synthetic Hf1a peptides were prepared with C-terminal amidation (Hf1a-NH₂) or a free C-terminus (Hf1a-OH). Electrophysiological characterization revealed Hf1a-NH₂ to be a concentration-dependent partial inhibitor of Ca_V3.2 (IC₅₀ = 1.18 μM) and Ca_V3.3 (IC₅₀ = 0.49 μM) depolarized currents but was ineffective at Ca_V3.1. Hf1a-OH did not show activity against any of the three T-type subtypes. Additionally, neither form showed activity against N-type Ca_V2.2 or L-type calcium channels. The three-dimensional structure of Hf1a-NH₂ was determined using NMR spectroscopy and used in docking studies to predict its binding site at Ca_V3.2 and Ca_V3.3. As both Ca_V3.2 and Ca_V3.3 have been implicated in peripheral pain signaling, the analgesic potential of Hf1a-NH₂ was explored in vivo in a mouse model of incision-induced acute post-surgical pain. Consistent with this role, Hf1a-NH₂ produced antiallodynia in both mechanical and thermal pain. Full article

(This article belongs to the Special Issue Regulatory Mechanisms of Ion Channels and Their Potential as Therapeutic Targets 2.0)

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17 pages, 3031 KiB

Open AccessArticle

Sustained Extracellular Electrical Stimulation Modulates the Permeability of Gap Junctions in rd1 Mouse Retina with Photoreceptor Degeneration

by Sophie Stürmer, Sylvia Bolz, Eberhart Zrenner, Marius Ueffing and Wadood Haq

Int. J. Mol. Sci. 2024, 25(3), 1616; https://doi.org/10.3390/ijms25031616 - 28 Jan 2024

Viewed by 1541

Abstract

Neurons build vast gap junction-coupled networks (GJ-nets) that are permeable to ions or small molecules, enabling lateral signaling. Herein, we investigate (1) the effect of blinding diseases on GJ-nets in mouse retinas and (2) the impact of electrical stimulation on GJ permeability. GJ permeability was traced in the acute retinal explants of blind retinal degeneration 1 (rd1) mice using the GJ tracer neurobiotin. The tracer was introduced via the edge cut method into the GJ-net, and its spread was visualized in histological preparations (fluorescent tagged) using microscopy. Sustained stimulation was applied to modulate GJ permeability using a single large electrode. Our findings are: (1) The blind rd1 retinas displayed extensive intercellular coupling via open GJs. Three GJ-nets were identified: horizontal, amacrine, and ganglion cell networks. (2) Sustained stimulation significantly diminished the tracer spread through the GJs in all the cell layers, as occurs with pharmaceutical inhibition with carbenoxolone. We concluded that the GJ-nets of rd1 retinas remain coupled and functional after blinding disease and that their permeability is regulatable by sustained stimulation. These findings are essential for understanding molecular signaling in diseases over coupled networks and therapeutic approaches using electrical implants, such as eliciting visual sensations or suppressing cortical seizures. Full article

(This article belongs to the Special Issue Regulatory Mechanisms of Ion Channels and Their Potential as Therapeutic Targets 2.0)

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16 pages, 25907 KiB

Open AccessArticle

Alpha-Mangostin: A Potent Inhibitor of TRPV3 and Pro-Inflammatory Cytokine Secretion in Keratinocytes

by Thi Huyen Dang, Ji Yeong Kim, Hyun Jong Kim, Byung Joo Kim, Woo Kyung Kim and Joo Hyun Nam

Int. J. Mol. Sci. 2023, 24(16), 12930; https://doi.org/10.3390/ijms241612930 - 18 Aug 2023

Cited by 6 | Viewed by 2111

Abstract

The TRPV3 calcium ion channel is vital for maintaining skin health and has been associated with various skin-related disorders. Since TRPV3 is involved in the development of skin inflammation, inhibiting TRPV3 could be a potential treatment strategy. Alpha-mangostin isolated from Garcinia mangostana L. extract exhibits diverse positive effects on skin health; however, the underlying mechanisms remain obscure. This study investigated the TRPV3-inhibitory properties of alpha-mangostin on TRPV3 hyperactive mutants associated with Olmsted syndrome and its impact on TRPV3-induced cytokine secretion and cell death. Our findings demonstrate that alpha-mangostin effectively inhibits TRPV3, with an IC₅₀ of 0.077 ± 0.013 μM, showing inhibitory effects on both wild-type and mutant TRPV3. TRPV3 inhibition with alpha-mangostin decreased calcium influx and cytokine release, protecting cells from TRPV3-induced death. These results indicate that alpha-mangostin reduced inflammation in TRPV3-activated skin keratinocytes, suggesting that alpha-mangostin could be potentially used for improving inflammatory skin conditions such as dermatitis. Full article

(This article belongs to the Special Issue Regulatory Mechanisms of Ion Channels and Their Potential as Therapeutic Targets 2.0)

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Review

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33 pages, 7574 KiB

Open AccessReview

Challenges in the Therapeutic Targeting of KCa Channels: From Basic Physiology to Clinical Applications

by Nhung Thi Hong Van, Woo Kyung Kim and Joo Hyun Nam

Int. J. Mol. Sci. 2024, 25(5), 2965; https://doi.org/10.3390/ijms25052965 - 4 Mar 2024

Cited by 4 | Viewed by 2113

Abstract

Calcium-activated potassium (KCa) channels are ubiquitously expressed throughout the body and are able to regulate membrane potential and intracellular calcium concentrations, thereby playing key roles in cellular physiology and signal transmission. Consequently, it is unsurprising that KCa channels have been implicated in various diseases, making them potential targets for pharmaceutical interventions. Over the past two decades, numerous studies have been conducted to develop KCa channel-targeting drugs, including those for disorders of the central and peripheral nervous, cardiovascular, and urinary systems and for cancer. In this review, we synthesize recent findings regarding the structure and activating mechanisms of KCa channels. We also discuss the role of KCa channel modulators in therapeutic medicine. Finally, we identify the major reasons behind the delay in bringing these modulators to the pharmaceutical market and propose new strategies to promote their application. Full article

(This article belongs to the Special Issue Regulatory Mechanisms of Ion Channels and Their Potential as Therapeutic Targets 2.0)

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