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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 (15 February 2023) | Viewed by 24473

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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,

Ion channels play important roles in cellular functions in various organ systems, such as the nervous, cardiovascular, immune, and endocrine systems, and are potential therapeutic targets for treatment of their dysfunction via ‘channelopathy’. Ion channels modulate diverse intracellular signaling pathways involved 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 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 channels and ion-related signaling are welcome, in particular molecular analyses of ion channels and their related intracellular signaling in multiple body systems are sought. It will also cover reports providing new insights into the molecular mechanisms of ‘channelopathy’, including the transcriptional, spliceosomal, epigenetic, and post-translational regulation of ion channels and the 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
cancer

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Published Papers (10 papers)

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Editorial

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3 pages, 192 KiB

Open AccessEditorial

Recent Developments in Ion Channel and Ion-Related Signaling

by Susumu Ohya

Int. J. Mol. Sci. 2023, 24(19), 14419; https://doi.org/10.3390/ijms241914419 - 22 Sep 2023

Cited by 2 | Viewed by 1654

Abstract

Ion channels play an important role in the cellular functions of various organ systems, such as the nervous, cardiovascular, immune, and endocrine systems, and are potential therapeutic targets for treatments of their dysfunctions, via ‘channelopathy’ [...] Full article

(This article belongs to the Special Issue Recent Developments in Ion Channel and Ion-Related Signaling)

Research

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15 pages, 2699 KiB

Open AccessArticle

Odorant Receptor OR2C1 Is an Essential Modulator of Boar Sperm Capacitation by Binding with Heparin

by Xiang Yuan, Yihan Wang, Malik Ahsan Ali, Ziyue Qin, Zhihua Guo, Yan Zhang, Ming Zhang, Guangbin Zhou, Jiandong Yang, Lei Chen, Linyuan Shen, Li Zhu and Changjun Zeng

Int. J. Mol. Sci. 2023, 24(2), 1664; https://doi.org/10.3390/ijms24021664 - 14 Jan 2023

Cited by 4 | Viewed by 2046

Abstract

Heparin, a class of glycosaminoglycans (GAGs), is widely used to induce sperm capacitation and fertilization. How heparin induces sperm capacitation remains unclear. Olfactory receptors (ORs) which are G protein-coupled receptors, have been proposed to be involved in sperm capacitation. However, the interaction between ORs and odor molecules and the molecular mechanism of ORs mediating sperm capacitation are still unclear. The present study aimed to explore the underlying interaction and mechanism between heparin and ORs in carrying out the boar sperm capacitation. The results showed that olfactory receptor 2C1 (OR2C1) is a compulsory unit which regulates the sperm capacitation by recognizing and binding with heparin, as determined by Dual-Glo Luciferase Assay and molecular docking. In addition, molecular dynamics (MD) simulation indicated that OR2C1 binds with heparin via a hydrophobic cavity comprises of Arg3, Ala6, Thr7, Asn171, Arg172, Arg173, and Pro287. Furthermore, we demonstrated that knocking down OR2C1 significantly inhibits sperm capacitation. In conclusion, we highlighted a novel olfactory receptor, OR2C1, in boar sperm and disclosed the potential binding of heparin to Pro287, a conserved residue in the transmembrane helices region 7 (TMH7). Our findings will benefit the further understanding of ORs involved in sperm capacitation and fertilization. Full article

(This article belongs to the Special Issue Recent Developments in Ion Channel and Ion-Related Signaling)

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13 pages, 3221 KiB

Open AccessArticle

Nuclear Factor of Activated T Cells-5 Regulates Notochord Lumenogenesis in Chordate Larval Development

by Muchun He, Jiankai Wei, Yuting Li and Bo Dong

Int. J. Mol. Sci. 2022, 23(22), 14407; https://doi.org/10.3390/ijms232214407 - 19 Nov 2022

Cited by 7 | Viewed by 1828

Abstract

Osmoregulation is essential for organisms to adapt to the exterior environment and plays an important role in embryonic organogenesis. Tubular organ formation usually involves a hyperosmotic lumen environment. The mechanisms of how the cells respond and regulate lumen formation remain largely unknown. Here, we reported that the nuclear factor of activated T cells-5 (NFAT5), the only transcription factor in the NFAT family involved in the cellular responses to hypertonic stress, regulated notochord lumen formation in chordate Ciona. Ciona NFAT5 (Ci-NFAT5) was expressed in notochord, and its expression level increased during notochord lumen formation and expansion. Knockout and expression of the dominant negative of NFAT5 in Ciona embryos resulted in the failure of notochord lumen expansion. We further demonstrated that the Ci-NFAT5 transferred from the cytoplasm into nuclei in HeLa cells under the hyperosmotic medium, indicating Ci-NFAT5 can respond the hypertonicity. To reveal the underly mechanisms, we predicted potential downstream genes of Ci-NFAT5 and further validated Ci-NFAT5-interacted genes by the luciferase assay. The results showed that Ci-NFAT5 promoted SLC26A6 expression. Furthermore, expression of a transport inactivity mutant of SLC26A6 (L421P) in notochord led to the failure of lumen expansion, phenocopying that of Ci-NFAT5 knockout. These results suggest that Ci-NFAT5 regulates notochord lumen expansion via the SLC26A6 axis. Taken together, our results reveal that the chordate NFAT5 responds to hypertonic stress and regulates lumen osmotic pressure via an ion channel pathway on luminal organ formation. Full article

(This article belongs to the Special Issue Recent Developments in Ion Channel and Ion-Related Signaling)

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15 pages, 2575 KiB

Open AccessArticle

Potent Activation of Human but Not Mouse TRPA1 by JT010

by Masaki Matsubara, Yukiko Muraki, Noriyuki Hatano, Hiroka Suzuki and Katsuhiko Muraki

Int. J. Mol. Sci. 2022, 23(22), 14297; https://doi.org/10.3390/ijms232214297 - 18 Nov 2022

Cited by 5 | Viewed by 2047

Abstract

Transient receptor potential (TRP) ankyrin repeat 1 (TRPA1), which is involved in inflammatory pain sensation, is activated by endogenous factors, such as intracellular Zn²⁺ and hydrogen peroxide, and by irritant chemical compounds. The synthetic compound JT010 potently and selectively activates human TRPA1 (hTRPA1) among the TRPs. Therefore, JT010 is a useful tool for analyzing TRPA1 functions in biological systems. Here, we show that JT010 is a potent activator of hTRPA1, but not mouse TRPA1 (mTRPA1) in human embryonic kidney (HEK) cells expressing hTRPA1 and mTRPA1. Application of 0.3–100 nM of JT010 to HEK cells with hTRPA1 induced large Ca²⁺ responses. However, in HEK cells with mTRPA1, the response was small. In contrast, both TRPA1s were effectively activated by allyl isothiocyanate (AITC) at 10–100 μM. Similar selective activation of hTRPA1 by JT010 was observed in electrophysiological experiments. Additionally, JT010 activated TRPA1 in human fibroblast-like synoviocytes with inflammation, but not TRPA1 in mouse dorsal root ganglion cells. As cysteine at 621 (C621) of hTRPA1, a critical cysteine for interaction with JT010, is conserved in mTRPA1, we applied JT010 to HEK cells with mutations in mTRPA1, where the different residue of mTRPA1 with tyrosine at 60 (Y60), with histidine at 1023 (H1023), and with asparagine at 1027 (N1027) were substituted with cysteine in hTRPA1. However, these mutants showed low sensitivity to JT010. In contrast, the mutation of hTRPA1 at position 669 from phenylalanine to methionine (F669M), comprising methionine at 670 in mTRPA1 (M670), significantly reduced the response to JT010. Moreover, the double mutant at S669 and M670 of mTRPA1 to S669E and M670F, respectively, induced slight but substantial sensitivity to 30 and 100 nM JT010. Taken together, our findings demonstrate that JT010 potently and selectively activates hTRPA1 but not mTRPA1. Full article

(This article belongs to the Special Issue Recent Developments in Ion Channel and Ion-Related Signaling)

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18 pages, 6172 KiB

Open AccessArticle

Downregulation of IL-8 and IL-10 by the Activation of Ca²⁺-Activated K⁺ Channel K_Ca3.1 in THP-1-Derived M₂ Macrophages

by Susumu Ohya, Miki Matsui, Junko Kajikuri, Hiroaki Kito and Kyoko Endo

Int. J. Mol. Sci. 2022, 23(15), 8603; https://doi.org/10.3390/ijms23158603 - 3 Aug 2022

Cited by 10 | Viewed by 2987

Abstract

THP-1-differentiated macrophages are useful for investigating the physiological significance of tumor-associated macrophages (TAMs). In the tumor microenvironment (TME), TAMs with the M₂-like phenotype play a critical role in promoting cancer progression and metastasis by inhibiting the immune surveillance system. We examined the involvement of Ca²⁺-activated K⁺ channel K_Ca3.1 in TAMs in expressing pro-tumorigenic cytokines and angiogenic growth factors. In THP-1-derived M₂ macrophages, the expression levels of IL-8 and IL-10 were significantly decreased by treatment with the selective K_Ca3.1 activator, SKA-121, without changes in those of VEGF and TGF-β1. Furthermore, under in vitro experimental conditions that mimic extracellular K⁺ levels in the TME, IL-8 and IL-10 levels were both significantly elevated, and these increases were reversed by combined treatment with SKA-121. Among several signaling pathways potentially involved in the transcriptional regulation of IL-8 and IL-10, respective treatments with ERK and JNK inhibitors significantly repressed their transcriptions, and treatment with SKA-121 significantly reduced the phosphorylated ERK, JNK, c-Jun, and CREB levels. These results strongly suggest that the K_Ca3.1 activator may suppress IL-10-induced tumor immune surveillance escape and IL-8-induced tumorigenicity and metastasis by inhibiting their production from TAMs through ERK-CREB and JNK-c-Jun cascades. Full article

(This article belongs to the Special Issue Recent Developments in Ion Channel and Ion-Related Signaling)

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10 pages, 1414 KiB

Open AccessCommunication

Neuropathic Pain Induces Interleukin-1β Sensitive Bimodal Glycinergic Activity in the Central Amygdala

by Carolina A. Oliva, Jimmy Stehberg, Rafael Barra and Trinidad Mariqueo

Int. J. Mol. Sci. 2022, 23(13), 7356; https://doi.org/10.3390/ijms23137356 - 1 Jul 2022

Cited by 4 | Viewed by 1600

Abstract

Neuropathic pain reduces GABA and glycine receptor (GlyR)-mediated activity in spinal and supraspinal regions associated with pain processing. Interleukin-1β (IL-1β) alters Central Amygdala (CeA) excitability by reducing glycinergic inhibition in a mechanism that involves the auxiliary β-subunit of GlyR (βGlyR), which is highly expressed in this region. However, GlyR activity and its modulation by IL-1β in supraspinal brain regions under neuropathic pain have not been studied. We performed chronic constriction injury (CCI) of the sciatic nerve in male Sprague Dawley rats, a procedure that induces hind paw plantar hyperalgesia and neuropathic pain. Ten days later, the rats were euthanized, and their brains were sliced. Glycinergic spontaneous inhibitory currents (sIPSCs) were recorded in the CeA slices. The sIPSCs from CeA neurons of CCI animals show a bimodal amplitude distribution, different from the normal distribution in Sham animals, with small and large amplitudes of similar decay constants. The perfusion of IL-1β (10 ng/mL) in these slices reduced the amplitudes within the first five minutes, with a pronounced effect on the largest amplitudes. Our data support a possible role for CeA GlyRs in pain processing and in the neuroimmune modulation of pain perception. Full article

(This article belongs to the Special Issue Recent Developments in Ion Channel and Ion-Related Signaling)

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19 pages, 9450 KiB

Open AccessArticle

Activation of TRPV4 Induces Exocytosis and Ferroptosis in Human Melanoma Cells

by Mei Li, Jiaojiao Zheng, Tian Wu, Yulin He, Jing Guo, Jiao Xu, Chuanzhou Gao, Shuxian Qu, Qianyi Zhang, Jiayu Zhao and Wei Cheng

Int. J. Mol. Sci. 2022, 23(8), 4146; https://doi.org/10.3390/ijms23084146 - 8 Apr 2022

Cited by 12 | Viewed by 2993

Abstract

TRPV4 (transient receptor potential vanilloid 4), a calcium permeable TRP ion channel, is known to play a key role in endocytosis. However, whether it contributes to exocytosis remains unclear. Here, we report that activation of TRPV4 induced massive exocytosis in both melanoma A375 cell and heterologous expression systems. We show here that, upon application of TRPV4-specific agonists, prominent vesicle priming from endoplasmic reticulum (ER) was observed, followed by morphological changes of mitochondrial crista may lead to cell ferroptosis. We further identified interactions between TRPV4 and folding/vesicle trafficking proteins, which were triggered by calcium entry through activated TRPV4. This interplay, in turn, enhanced TRPV4-mediated activation of folding and vesicle trafficking proteins to promote exocytosis. Our study revealed a signaling mechanism underlying stimulus-triggered exocytosis in melanoma and highlighted the role of cellular sensor TRPV4 ion channel in mediating ferroptosis. Full article

(This article belongs to the Special Issue Recent Developments in Ion Channel and Ion-Related Signaling)

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13 pages, 2242 KiB

Open AccessArticle

Sodium Nitroprusside-Induced Activation of Vascular Smooth Muscle BK Channels Is Mediated by PKG Rather Than by a Direct Interaction with NO

by Hristo Gagov, Irina V. Gribkova, Vladimir N. Serebryakov and Rudolf Schubert

Int. J. Mol. Sci. 2022, 23(5), 2798; https://doi.org/10.3390/ijms23052798 - 3 Mar 2022

Cited by 9 | Viewed by 2524

Abstract

Nitric oxide (NO) is a powerful vasodilator in different vascular beds and NO-donors are widely used in clinical practice. Early data suggested that NO and NO-donors activate vascular smooth muscle high-conductance, calcium-activated potassium channels (BK channels). There exist two hypotheses explaining the effect of NO and NO-donors on BK channels—one stating that protein kinase G (PKG) mediates the effect of NO, and the other one stating that NO acts directly on the channel. Thus, the degree of contribution of PKG to the NO-induced activation of the BK channel is still not completely clear. This study tested the hypothesis that the sodium nitroprusside (SNP)-induced activation of vascular smooth muscle BK channels is fully mediated by PKG. This hypothesis was investigated using the patch-clamp technique and freshly isolated smooth muscle cells from rat tail artery. In whole-cell experiments, SNP considerably increased the outward current compared with the addition of the bath solution. SNP did not alter the current in the presence of iberiotoxin, the specific blocker of BK channels, during co-application with hydroxocobalamin, an NO-scavenger, and in the presence of Rp-8-Br-PET-cGMPS, the specific PKG-inhibitor. In inside-out patches, the activity of BK channels was increased by SNP, SNAP, and DEA-NO. However, these effects did not differ from the effect of the application of drug-free bath solution. Furthermore, a similar increase in single BK channel activity was induced by Rp-8-Br-PET-cGMPS, Rp-8-Br-PET-cGMPS together with SNP, hydroxocobalamin, and hydroxocobalamin together with SNP or DEA-NO. Finally, the activity of excised BK channels did not change in the absence of any application but was considerably increased by PKG compared with the addition of drug-free bath solution. These results suggest that NO released from NO-donors stimulates the BK current only through activation of PKG. Full article

(This article belongs to the Special Issue Recent Developments in Ion Channel and Ion-Related Signaling)

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Review

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22 pages, 2024 KiB

Open AccessReview

Astrocytic TRPV4 Channels and Their Role in Brain Ischemia

by Jana Tureckova, Zuzana Hermanova, Valeria Marchetti and Miroslava Anderova

Int. J. Mol. Sci. 2023, 24(8), 7101; https://doi.org/10.3390/ijms24087101 - 12 Apr 2023

Cited by 12 | Viewed by 2879

Abstract

Transient receptor potential cation channels subfamily V member 4 (TRPV4) are non-selective cation channels expressed in different cell types of the central nervous system. These channels can be activated by diverse physical and chemical stimuli, including heat and mechanical stress. In astrocytes, they are involved in the modulation of neuronal excitability, control of blood flow, and brain edema formation. All these processes are significantly impaired in cerebral ischemia due to insufficient blood supply to the tissue, resulting in energy depletion, ionic disbalance, and excitotoxicity. The polymodal cation channel TRPV4, which mediates Ca²⁺ influx into the cell because of activation by various stimuli, is one of the potential therapeutic targets in the treatment of cerebral ischemia. However, its expression and function vary significantly between brain cell types, and therefore, the effect of its modulation in healthy tissue and pathology needs to be carefully studied and evaluated. In this review, we provide a summary of available information on TRPV4 channels and their expression in healthy and injured neural cells, with a particular focus on their role in ischemic brain injury. Full article

(This article belongs to the Special Issue Recent Developments in Ion Channel and Ion-Related Signaling)

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16 pages, 1922 KiB

Open AccessReview

New Insights into TRP Ion Channels in Stem Cells

by Jing Guo, Chang Shan, Jiao Xu, Mei Li, Jiayu Zhao and Wei Cheng

Int. J. Mol. Sci. 2022, 23(14), 7766; https://doi.org/10.3390/ijms23147766 - 14 Jul 2022

Cited by 6 | Viewed by 2501

Abstract

Transient receptor potential (TRP) ion channels are cationic permeable proteins located on the plasma membrane. TRPs are cellular sensors for perceiving diverse physical and/or chemical stimuli; thus, serving various critical physiological functions, including chemo-sensation, hearing, homeostasis, mechano-sensation, pain, taste, thermoregulation, vision, and even carcinogenesis. Dysregulated TRPs are found to be linked to many human hereditary diseases. Recent studies indicate that TRP ion channels are not only involved in sensory functions but are also implicated in regulating the biological characteristics of stem cells. In the present review, we summarize the expressions and functions of TRP ion channels in stem cells, including cancer stem cells. It offers an overview of the current understanding of TRP ion channels in stem cells. Full article

(This article belongs to the Special Issue Recent Developments in Ion Channel and Ion-Related Signaling)

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