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Ion Channel and Ion-Related Signaling 2019

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 39736

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Prof. Dr. Susumu Ohya

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Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Mizuho-ku, Nagoya 467-8601, Japan
Interests: molecular pharmacological study of ion channel related diseases
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Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our 2018 Special Issue, “Ion Channel and Ion-Related Signaling”.

Ion channels play important roles in cellular functions in various organ systems, such as nervous, cardiovascular, immune, and endocrine systems, and are potential therapeutic targets for treatment of their dysfunction “Channelopathy”. Ion channels modulate diverse intracellular signaling pathways involving in neuronal activity, muscle contraction, cell proliferation, differentiation, apoptosis, and transcription. In addition, ion channel regulatory proteins alter electrophysiological characteristics, cellular localization/membrane trafficking, and drug sensitivity of ion channels, and contribute to the functional diversity and cell-specific responses. Organellar ion channels in the endoplasmic/sarcoplasmic reticulum and mitochondrial inner membrane are also focused on new therapeutic targets in cellular function and dysfunction.

In this Special Issue, original studies on all aspects of ion channel and ion-related signaling are welcome and in particular, molecular analyses of ion channels and their related intracellular signaling in multiple body systems are favorable. It will also cover the reports providing new insights into molecular mechanisms of “Channelopathies”, including the transcriptional, spliceosomal, epigenetic, and post-translational regulation of ion channels and impact of novel screening technologies on ion channel drug discovery.

Prof. Dr. Susumu Ohya
Guest Editor

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Keywords

ion channel
Ca²⁺ signaling
channelopathy
mitochondria ion channel
lipid raft
cardiovascular disease
immune disease
membrane trafficking
epigenetics
post-translational regulation

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Ion Channel and Ion-Related Signaling 2020 in International Journal of Molecular Sciences (19 articles)

Published Papers (9 papers)

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Research

16 pages, 4505 KiB

Open AccessArticle

Possible Contribution of Inflammation-Associated Hypoxia to Increased K_2P5.1 K⁺ Channel Expression in CD4⁺ T Cells of the Mouse Model for Inflammatory Bowel Disease

by Kyoko Endo, Hiroaki Kito, Ryo Tanaka, Junko Kajikuri, Satoshi Tanaka, Elghareeb E. Elboray, Takayoshi Suzuki and Susumu Ohya

Int. J. Mol. Sci. 2020, 21(1), 38; https://doi.org/10.3390/ijms21010038 - 19 Dec 2019

Cited by 7 | Viewed by 3866

Abstract

Previous studies have reported the up-regulation of the two-pore domain K⁺ channel K_2P5.1 in the CD4⁺ T cells of patients with multiple sclerosis (MS) and rheumatoid arthritis (RA), as well as in a mouse model of inflammatory bowel disease (IBD). However, the mechanisms underlying this up-regulation remain unclear. Inflammation-associated hypoxia is involved in the pathogenesis of autoimmune diseases, such as IBD, MS, and RA, and T cells are exposed to a hypoxic environment during their recruitment from inflamed tissues to secondary lymphoid tissues. We herein investigated whether inflammation-associated hypoxia is attributable to the increased expression and activity of K_2P5.1 in the splenic CD4⁺ T cells of chemically-induced IBD model mice. Significant increases in hypoxia-inducible factor (HIF)-1α transcripts and proteins were found in the splenic CD4⁺ T cells of the IBD model. In the activated splenic CD4⁺ T cells, hypoxia (1.5% O₂) increased K_2P5.1 expression and activity, whereas a treatment with the HIF inhibitor FM19G11 but not the selective HIF-2 inhibitor exerted the opposite effect. Hypoxia-exposed K_2P5.1 up-regulation was also detected in stimulated thymocytes and the mouse T-cell line. The class III histone deacetylase sirtuin-1 (SIRT1) is a downstream molecule of HIF-1α signaling. We examined the effects of the SIRT1 inhibitor NCO-01 on K_2P5.1 transcription in activated CD4⁺ T cells, and we found no significant effects on the K_2P5.1 transcription. No acute compensatory responses of K_2P3.1–K_2P5.1 up-regulation were found in the CD4⁺ T cells of the IBD model and the hypoxia-exposed T cells. Collectively, these results suggest a mechanism for K_2P5.1 up-regulation via HIF-1 in the CD4⁺ T cells of the IBD model. Full article

(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling 2019)

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15 pages, 4579 KiB

Open AccessArticle

Windup of Nociceptive Flexion Reflex Depends on Synaptic and Intrinsic Properties of Dorsal Horn Neurons in Adult Rats

by Franck Aby, Rabia Bouali-Benazzouz, Marc Landry and Pascal Fossat

Int. J. Mol. Sci. 2019, 20(24), 6146; https://doi.org/10.3390/ijms20246146 - 5 Dec 2019

Cited by 5 | Viewed by 3637

Abstract

Windup, a progressive increase in spinal response to repetitive stimulations of nociceptive peripheral fibers, is a useful model to study central sensitization to pain. Windup is expressed by neurons in both the dorsal and ventral horn of the spinal cord. In juvenile rats, it has been demonstrated both in vivo and in vitro that windup depends on calcium-dependent intrinsic properties and their modulation by synaptic components. However, the involvement of these two components in the adults remains controversial. In the present study, by means of electromyographic and extracellular recordings, we show that windup in adults, in vivo, depends on a synaptic balance between excitatory N-methyl-D-aspartate (NMDA) receptors and inhibitory glycinergic receptors. We also demonstrate the involvement of L-type calcium channels in both the dorsal and ventral horn of the spinal cord. These results indicate that windup in adults is similar to juvenile rats and that windup properties are the same regardless of the spinal network, i.e., sensory or motor. Full article

(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling 2019)

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12 pages, 1951 KiB

Open AccessArticle

RBM20 Regulates CaV1.2 Surface Expression by Promoting Exon 9* Inclusion of CACNA1C in Neonatal Rat Cardiomyocytes

by Akihito Morinaga, Jumpei Ito, Tomoaki Niimi and Andrés D. Maturana

Int. J. Mol. Sci. 2019, 20(22), 5591; https://doi.org/10.3390/ijms20225591 - 8 Nov 2019

Cited by 6 | Viewed by 3280

Abstract

The CACNA1C gene encodes for the CaV1.2 protein, which is the pore subunit of cardiac l-type voltage-gated calcium (Ca²⁺) channels (l-channels). Through alternative splicing, CACNA1C encodes for various CaV1.2 isoforms with different electrophysiological properties. Splice variants of CaV1.2 are differentially expressed during heart development or pathologies. The molecular mechanisms of CACNA1C alternative splicing still remain incompletely understood. RNA sequencing analysis has suggested that CACNA1C is a potential target of the splicing factor RNA-binding protein motif 20 (RBM20). Here, we aimed at elucidating the role of RBM20 in the regulation of CACNA1C alternative splicing. We found that in neonatal rat cardiomyocytes (NRCMs), RBM20 overexpression promoted the inclusion of CACNA1C’s exon 9*, whereas the skipping of exon 9* occurred upon RBM20 siRNA knockdown. The splicing of other known alternative exons was not altered by RBM20. RNA immunoprecipitation suggested that RBM20 binds to introns flanking exon 9*. Functionally, in NRCMs, RBM20 overexpression decreased l-type Ca²⁺ currents, whereas RBM20 siRNA knockdown increased l-type Ca²⁺ currents. Finally, we found that RBM20 overexpression reduced CaV1.2 membrane surface expression in NRCMs. Taken together, our results suggest that RBM20 specifically regulates the inclusion of exon 9* in CACNA1C mRNA, resulting in reduced cell-surface membrane expression of l-channels in cardiomyocytes. Full article

(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling 2019)

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18 pages, 2965 KiB

Open AccessArticle

Single-Channel Properties of the ROMK-Pore-Forming Subunit of the Mitochondrial ATP-Sensitive Potassium Channel

by Michał Laskowski, Bartłomiej Augustynek, Piotr Bednarczyk, Monika Żochowska, Justyna Kalisz, Brian O’Rourke, Adam Szewczyk and Bogusz Kulawiak

Int. J. Mol. Sci. 2019, 20(21), 5323; https://doi.org/10.3390/ijms20215323 - 25 Oct 2019

Cited by 32 | Viewed by 4784

Abstract

An increased flux of potassium ions into the mitochondrial matrix through the ATP-sensitive potassium channel (mitoK_ATP) has been shown to provide protection against ischemia-reperfusion injury. Recently, it was proposed that the mitochondrial-targeted isoform of the renal outer medullary potassium channel (ROMK) protein creates a pore-forming subunit of mitoK_ATP in heart mitochondria. Our research focuses on the properties of mitoK_ATP from heart-derived H9c2 cells. For the first time, we detected single-channel activity and describe the pharmacology of mitoK_ATP in the H9c2 heart-derived cells. The patch-clamping of mitoplasts from wild type (WT) and cells overexpressing ROMK2 revealed the existence of a potassium channel that exhibits the same basic properties previously attributed to mitoK_ATP. ROMK2 overexpression resulted in a significant increase of mitoK_ATP activity. The conductance of both channels in symmetric 150/150 mM KCl was around 97 ± 2 pS in WT cells and 94 ± 3 pS in cells overexpressing ROMK2. The channels were inhibited by 5-hydroxydecanoic acid (a mitoK_ATP inhibitor) and by Tertiapin Q (an inhibitor of both the ROMK-type channels and mitoK_ATP). Additionally, mitoK_ATP from cells overexpressing ROMK2 were inhibited by ATP/Mg²⁺ and activated by diazoxide. We used an assay based on proteinase K to examine the topology of the channel in the inner mitochondrial membrane and found that both termini of the protein localized to the mitochondrial matrix. We conclude that the observed activity of the channel formed by the ROMK protein corresponds to the electrophysiological and pharmacological properties of mitoK_ATP. Full article

(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling 2019)

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19 pages, 2798 KiB

Open AccessArticle

Functional Consequences of the SCN5A-p.Y1977N Mutation within the PY Ubiquitylation Motif: Discrepancy between HEK293 Cells and Transgenic Mice

by Simona Casini, Maxime Albesa, Zizun Wang, Vincent Portero, Daniela Ross-Kaschitza, Jean-Sébastien Rougier, Gerard A. Marchal, Wendy K. Chung, Connie R. Bezzina, Hugues Abriel and Carol Ann Remme

Int. J. Mol. Sci. 2019, 20(20), 5033; https://doi.org/10.3390/ijms20205033 - 11 Oct 2019

Cited by 9 | Viewed by 4150

Abstract

Dysfunction of the cardiac sodium channel Nav1.5 (encoded by the SCN5A gene) is associated with arrhythmias and sudden cardiac death. SCN5A mutations associated with long QT syndrome type 3 (LQT3) lead to enhanced late sodium current and consequent action potential (AP) prolongation. Internalization and degradation of Na_v1.5 is regulated by ubiquitylation, a post-translational mechanism that involves binding of the ubiquitin ligase Nedd4-2 to a proline-proline-serine-tyrosine sequence of Na_v1.5, designated the PY-motif. We investigated the biophysical properties of the LQT3-associated SCN5A-p.Y1977N mutation located in the Na_v1.5 PY-motif, both in HEK293 cells as well as in newly generated mice harboring the mouse homolog mutation Scn5a-p.Y1981N. We found that in HEK293 cells, the SCN5A-p.Y1977N mutation abolished the interaction between Na_v1.5 and Nedd4-2, suppressed PY-motif-dependent ubiquitylation of Na_v1.5, and consequently abrogated Nedd4-2 induced sodium current (I_Na) decrease. Nevertheless, homozygous mice harboring the Scn5a-p.Y1981N mutation showed no electrophysiological alterations nor changes in AP or (late) I_Na properties, questioning the in vivo relevance of the PY-motif. Our findings suggest the presence of compensatory mechanisms, with additional, as yet unknown, factors likely required to reduce the “ubiquitylation reserve” of Na_v1.5. Future identification of such modulatory factors may identify potential triggers for arrhythmias and sudden cardiac death in the setting of LQT3 mutations. Full article

(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling 2019)

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20 pages, 3535 KiB

Open AccessArticle

PIEZO1 and TRPV4, which Are Distinct Mechano-Sensors in the Osteoblastic MC3T3-E1 Cells, Modify Cell-Proliferation

by Maki Yoneda, Hiroka Suzuki, Noriyuki Hatano, Sayumi Nakano, Yukiko Muraki, Ken Miyazawa, Shigemi Goto and Katsuhiko Muraki

Int. J. Mol. Sci. 2019, 20(19), 4960; https://doi.org/10.3390/ijms20194960 - 8 Oct 2019

Cited by 65 | Viewed by 7220

Abstract

Mechanical-loading and unloading can modify osteoblast functioning. Ca²⁺ signaling is one of the earliest events in osteoblasts to induce a mechanical stimulus, thereby demonstrating the importance of the underlying mechanical sensors for the sensation. Here, we examined the mechano-sensitive channels PIEZO1 and TRPV4 were involved in the process of mechano-sensation in the osteoblastic MC3T3-E1 cells. The analysis of mRNA expression revealed a high expression of Piezo1 and Trpv4 in these cells. We also found that a PIEZO1 agonist, Yoda1, induced Ca²⁺ response and activated cationic currents in these cells. Ca²⁺ response was elicited when mechanical stimulation (MS), with shear stress, was induced by fluid flow in the MC3T3-E1 cells. Gene knockdown of Piezo1 in the MC3T3-E1 cells, by transfection with siPiezo1, inhibited the Yoda1-induced response, but failed to inhibit the MS-induced response. When MC3T3-E1 cells were transfected with siTrpv4, the MS-induced response was abolished and Yoda1 response was attenuated. Moreover, the MS-induced response was inhibited by a TRPV4 antagonist HC-067047 (HC). Yoda1 response was also inhibited by HC in MC3T3-E1 cells and HEK cells, expressing both PIEZO1 and TRPV4. Meanwhile, the activation of PIEZO1 and TRPV4 reduced the proliferation of MC3T3-E1, which was reversed by knockdown of PIEZO1, and TRPV4, respectively. In conclusion, TRPV4 and PIEZO1 are distinct mechano-sensors in the MC3T3-E1 cells. However, PIEZO1 and TRPV4 modify the proliferation of these cells, implying that PIEZO1 and TRPV4 may be functional in the osteoblastic mechano-transduction. Notably, it is also found that Yoda1 can induce TRPV4-dependent Ca²⁺ response, when both PIEZO1 and TRPV4 are highly expressed. Full article

(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling 2019)

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14 pages, 2247 KiB

Open AccessArticle

Castration Induces Down-Regulation of A-Type K⁺ Channel in Rat Vas Deferens Smooth Muscle

by Susumu Ohya, Katsunori Ito, Noriyuki Hatano, Akitoshi Ohno, Katsuhiko Muraki and Yuji Imaizumi

Int. J. Mol. Sci. 2019, 20(17), 4073; https://doi.org/10.3390/ijms20174073 - 21 Aug 2019

Cited by 3 | Viewed by 3193

Abstract

A-type K⁺ channels contribute to regulating the propagation and frequency of action potentials in smooth muscle cells (SMCs). The present study (i) identified the molecular components of A-type K⁺ channels in rat vas deferens SMs (VDSMs) and (ii) showed the long-term, genomic effects of testosterone on their expression in VDSMs. Transcripts of the A-type K⁺ channel α subunit, Kv4.3L and its regulatory β subunits, KChIP3, NCS1, and DPP6-S were predominantly expressed in rat VDSMs over the other related subtypes (Kv4.2, KChIP1, KChIP2, KChIP4, and DPP10). A-type K⁺ current (I_A) density in VDSM cells (VDSMCs) was decreased by castration without changes in I_A kinetics, and decreased I_A density was compensated for by an oral treatment with 17α-methyltestosterone (MET). Correspondingly, in the VDSMs of castrated rats, Kv4.3L and KChIP3 were down-regulated at both the transcript and protein expression levels. Changes in Kv4.3L and KChIP3 expression levels were compensated for by the treatment with MET. These results suggest that testosterone level changes in testosterone disorders and growth processes control the functional expression of A-type K⁺ channels in VDSMCs. Full article

(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling 2019)

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15 pages, 4594 KiB

Open AccessArticle

Formation Mechanism of Ion Channel in Channelrhodopsin-2: Molecular Dynamics Simulation and Steering Molecular Dynamics Simulations

by Ting Yang, Wenying Zhang, Jie Cheng, Yanhong Nie, Qi Xin, Shuai Yuan and Yusheng Dou

Int. J. Mol. Sci. 2019, 20(15), 3780; https://doi.org/10.3390/ijms20153780 - 2 Aug 2019

Cited by 12 | Viewed by 4760

Abstract

Channelrhodopsin-2 (ChR2) is a light-activated and non-selective cationic channel protein that can be easily expressed in specific neurons to control neuronal activity by light. Although ChR2 has been extensively used as an optogenetic tool in neuroscience research, the molecular mechanism of cation channel formation following retinal photoisomerization in ChR2 is not well understood. In this paper, studies of the closed and opened state ChR2 structures are presented. The formation of the cationic channel is elucidated in atomic detail using molecular dynamics simulations on the all-trans-retinal (ChR2-trans) configuration of ChR2 and its isomerization products, 13-cis-retinal (ChR2-cis) configuration, respectively. Photoisomerization of the retinal-chromophore causes the destruction of interactions among the crucial residues (e.g., E90, E82, N258, and R268) around the channel and the extended H-bond network mediated by numerous water molecules, which opens the pore. Steering molecular dynamics (SMD) simulations show that the electrostatic interactions at the binding sites in intracellular gate (ICG) and central gate (CG) can influence the transmembrane transport of Na⁺ in ChR2-cis obviously. Potential of mean force (PMF) constructed by SMD and umbrella sampling also found the existing energy wells at these two binding sites during the transportation of Na⁺. These wells partly hinder the penetration of Na⁺ into cytoplasm through the ion channel. This investigation provides a theoretical insight on the formation mechanism of ion channels and the mechanism of ion permeation. Full article

(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling 2019)

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14 pages, 2102 KiB

Open AccessArticle

Extracellular l-arginine Enhances Relaxations Induced by Opening of Calcium-Activated SKCa Channels in Porcine Retinal Arteriole

by Ulf Simonsen, Anna K. Winther, Aida Oliván-Viguera, Simon Comerma-Steffensen, Ralf Köhler and Toke Bek

Int. J. Mol. Sci. 2019, 20(8), 2032; https://doi.org/10.3390/ijms20082032 - 25 Apr 2019

Cited by 1 | Viewed by 4158

Abstract

We investigated whether the substrate for nitric oxide (NO) production, extracellular l-arginine, contributes to relaxations induced by activating small (SKCa) conductance Ca²⁺-activated potassium channels. In endothelial cells, acetylcholine increased ³H-l-arginine uptake, while blocking the SKCa and the intermediate (IKCa) conductance Ca²⁺-activated potassium channels reduced l-arginine uptake. A blocker of the y+ transporter system, l-lysine also blocked ³H-l-arginine uptake. Immunostaining showed co-localization of endothelial NO synthase (eNOS), SKCa3, and the cationic amino acid transporter (CAT-1) protein of the y+ transporter system in the endothelium. An opener of SKCa channels, cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) induced large currents in endothelial cells, and concentration-dependently relaxed porcine retinal arterioles. In the presence of l-arginine, concentration-response curves for CyPPA were leftward shifted, an effect unaltered in the presence of low sodium, but blocked by l-lysine in the retinal arterioles. Our findings suggest that SKCa channel activity regulates l-arginine uptake through the y+ transporter system, and we propose that in vasculature affected by endothelial dysfunction, l-arginine administration requires the targeting of additional mechanisms such as SKCa channels to restore endothelium-dependent vasodilatation. Full article

(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling 2019)

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