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Ion Channel and Ion-Related Signaling

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 2018) | Viewed by 78443

Special Issue Editors

Cellular Pharmacology, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650, Japan
Interests: ion channel and transporter research

Special Issue Information

Dear Colleagues,

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
Prof. Dr. Katsuhiko Muraki
Guest Editors

Manuscript Submission Information

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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

Published Papers (14 papers)

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Research

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18 pages, 2010 KiB  
Article
The Effects of a Combination of Ion Channel Inhibitors in Female Rats Following Repeated Mild Traumatic Brain Injury
by Yilin Mao, Anna M. B. Black, Hannah R. Milbourn, Samra Krakonja, Michael Nesbit, Carole A. Bartlett, Brooke Fehily, Ryu Takechi, Nathanael J. Yates and Melinda Fitzgerald
Int. J. Mol. Sci. 2018, 19(11), 3408; https://doi.org/10.3390/ijms19113408 - 31 Oct 2018
Cited by 15 | Viewed by 3341
Abstract
Following mild traumatic brain injury (mTBI), the ionic homeostasis of the central nervous system (CNS) becomes imbalanced. Excess Ca2+ influx into cells triggers molecular cascades, which result in detrimental effects. The authors assessed the effects of a combination of ion channel inhibitors [...] Read more.
Following mild traumatic brain injury (mTBI), the ionic homeostasis of the central nervous system (CNS) becomes imbalanced. Excess Ca2+ influx into cells triggers molecular cascades, which result in detrimental effects. The authors assessed the effects of a combination of ion channel inhibitors (ICI) following repeated mTBI (rmTBI). Adult female rats were subjected to two rmTBI weight-drop injuries 24 h apart, sham procedures (sham), or no procedures (normal). Lomerizine, which inhibits voltage-gated calcium channels, was administered orally twice daily, whereas YM872 and Brilliant Blue G, inhibiting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and P2X7 receptors, respectively, were delivered intraperitoneally every 48 h post-injury. Vehicle treatment controls were included for rmTBI, sham, and normal groups. At 11 days following rmTBI, there was a significant increase in the time taken to cross the 3 cm beam, as a sub-analysis of neurological severity score (NSS) assessments, compared with the normal control (p < 0.05), and a significant decrease in learning-associated improvement in rmTBI in Morris water maze (MWM) trials relative to the sham (p < 0.05). ICI-treated rmTBI animals were not different to sham, normal controls, or rmTBI treated with vehicle in all neurological severity score and Morris water maze assessments (p > 0.05). rmTBI resulted in increases in microglial cell density, antioxidant responses (manganese-dependent superoxide dismutase (MnSOD) immunoreactivity), and alterations to node of Ranvier structure. ICI treatment decreased microglial density, MnSOD immunoreactivity, and abnormalities of the node of Ranvier compared with vehicle controls (p < 0.01). The authors’ findings demonstrate the beneficial effects of the combinatorial ICI treatment on day 11 post-rmTBI, suggesting an attractive therapeutic strategy against the damage induced by excess Ca2+ following rmTBI. Full article
(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling)
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20 pages, 4059 KiB  
Article
The 2β Splice Variation Alters the Structure and Function of the Stromal Interaction Molecule Coiled-Coil Domains
by Steve Chung, MengQi Zhang and Peter B. Stathopulos
Int. J. Mol. Sci. 2018, 19(11), 3316; https://doi.org/10.3390/ijms19113316 - 25 Oct 2018
Cited by 8 | Viewed by 3642
Abstract
Stromal interaction molecule (STIM)-1 and -2 regulate agonist-induced and basal cytosolic calcium (Ca2+) levels after oligomerization and translocation to endoplasmic reticulum (ER)-plasma membrane (PM) junctions. At these junctions, the STIM cytosolic coiled-coil (CC) domains couple to PM Orai1 proteins and gate [...] Read more.
Stromal interaction molecule (STIM)-1 and -2 regulate agonist-induced and basal cytosolic calcium (Ca2+) levels after oligomerization and translocation to endoplasmic reticulum (ER)-plasma membrane (PM) junctions. At these junctions, the STIM cytosolic coiled-coil (CC) domains couple to PM Orai1 proteins and gate these Ca2+ release-activated Ca2+ (CRAC) channels, which facilitate store-operated Ca2+ entry (SOCE). Unlike STIM1 and STIM2, which are SOCE activators, the STIM2β splice variant contains an 8-residue insert located within the conserved CCs which inhibits SOCE. It remains unclear if the 2β insert further depotentiates weak STIM2 coupling to Orai1 or independently causes structural perturbations which prevent SOCE. Here, we use far-UV circular dichroism, light scattering, exposed hydrophobicity analysis, solution small angle X-ray scattering, and a chimeric STIM1/STIM2β functional assessment to provide insights into the molecular mechanism by which the 2β insert precludes SOCE activation. We find that the 2β insert reduces the overall α-helicity and enhances the exposed hydrophobicity of the STIM2 CC domains in the absence of a global conformational change. Remarkably, incorporation of the 2β insert into the STIM1 context not only affects the secondary structure and hydrophobicity as observed for STIM2, but also eliminates the more robust SOCE response mediated by STIM1. Collectively, our data show that the 2β insert directly precludes Orai1 channel activation by inducing structural perturbations in the STIM CC region. Full article
(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling)
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15 pages, 3305 KiB  
Article
Histone Deacetylases Enhance Ca2+-Activated K+ Channel KCa3.1 Expression in Murine Inflammatory CD4+ T Cells
by Miki Matsui, Kyoko Terasawa, Junko Kajikuri, Hiroaki Kito, Kyoko Endo, Pattaporn Jaikhan, Takayoshi Suzuki and Susumu Ohya
Int. J. Mol. Sci. 2018, 19(10), 2942; https://doi.org/10.3390/ijms19102942 - 27 Sep 2018
Cited by 13 | Viewed by 3481
Abstract
The up-regulated expression of the Ca2+-activated K+ channel KCa3.1 in inflammatory CD4+ T cells has been implicated in the pathogenesis of inflammatory bowel disease (IBD) through the enhanced production of inflammatory cytokines, such as interferon-γ (IFN-γ). However, [...] Read more.
The up-regulated expression of the Ca2+-activated K+ channel KCa3.1 in inflammatory CD4+ T cells has been implicated in the pathogenesis of inflammatory bowel disease (IBD) through the enhanced production of inflammatory cytokines, such as interferon-γ (IFN-γ). However, the underlying mechanisms have not yet been elucidated. The objective of the present study is to clarify the involvement of histone deacetylases (HDACs) in the up-regulation of KCa3.1 in the CD4+ T cells of IBD model mice. The expression levels of KCa3.1 and its regulators, such as function-modifying molecules and transcription factors, were quantitated using a real-time polymerase chain reaction (PCR) assay, Western blotting, and depolarization responses, which were induced by the selective KCa3.1 blocker TRAM-34 (1 μM) and were measured using a voltage-sensitive fluorescent dye imaging system. The treatment with 1 μM vorinostat, a pan-HDAC inhibitor, for 24 h repressed the transcriptional expression of KCa3.1 in the splenic CD4+ T cells of IBD model mice. Accordingly, TRAM-34-induced depolarization responses were significantly reduced. HDAC2 and HDAC3 were significantly up-regulated in the CD4+ T cells of IBD model mice. The down-regulated expression of KCa3.1 was observed following treatments with the selective inhibitors of HDAC2 and HDAC3. The KCa3.1 K+ channel regulates inflammatory cytokine production in CD4+ T cells, mediating epigenetic modifications by HDAC2 and HDAC3. Full article
(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling)
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15 pages, 1754 KiB  
Article
MicroRNA-204 Is Necessary for Aldosterone-Stimulated T-Type Calcium Channel Expression in Cardiomyocytes
by Riko Koyama, Tiphaine Mannic, Jumpei Ito, Laurence Amar, Maria-Christina Zennaro, Michel Florian Rossier and Andrés Daniel Maturana
Int. J. Mol. Sci. 2018, 19(10), 2941; https://doi.org/10.3390/ijms19102941 - 27 Sep 2018
Cited by 11 | Viewed by 3319
Abstract
Activation of the mineralocorticoid receptor (MR) in the heart is considered to be a cardiovascular risk factor. MR activation leads to heart hypertrophy and arrhythmia. In ventricular cardiomyocytes, aldosterone induces a profound remodeling of ion channel expression, in particular, an increase in the [...] Read more.
Activation of the mineralocorticoid receptor (MR) in the heart is considered to be a cardiovascular risk factor. MR activation leads to heart hypertrophy and arrhythmia. In ventricular cardiomyocytes, aldosterone induces a profound remodeling of ion channel expression, in particular, an increase in the expression and activity of T-type voltage-gated calcium channels (T-channels). The molecular mechanisms immediately downstream from MR activation, which lead to the increased expression of T-channels and, consecutively, to an acceleration of spontaneous cell contractions in vitro, remain poorly investigated. Here, we investigated the putative role of a specific microRNA in linking MR activation to the regulation of T-channel expression and cardiomyocyte beating frequency. A screening assay identified microRNA 204 (miR-204) as one of the major upregulated microRNAs after aldosterone stimulation of isolated neonatal rat cardiomyocytes. Aldosterone significantly increased the level of miR-204, an effect blocked by the MR antagonist spironolactone. When miR-204 was overexpressed in isolated cardiomyocytes, their spontaneous beating frequency was significantly increased after 24 h, like upon aldosterone stimulation, and messenger RNAs coding T-channels (CaV3.1 and CaV3.2) were increased. Concomitantly, T-type calcium currents were significantly increased upon miR-204 overexpression. Specifically repressing the expression of miR-204 abolished the aldosterone-induced increase of CaV3.1 and CaV3.2 mRNAs, as well as T-type calcium currents. Finally, aldosterone and miR-204 overexpression were found to reduce REST-NRSF, a known transcriptional repressor of CaV3.2 T-type calcium channels. Our study thus strongly suggests that miR-204 expression stimulated by aldosterone promotes the expression of T-channels in isolated rat ventricular cardiomyocytes, and therefore, increases the frequency of the cell spontaneous contractions, presumably through the inhibition of REST-NRSF protein. Full article
(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling)
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13 pages, 6437 KiB  
Article
Ca2+ Signaling and IL-8 Secretion in Human Testicular Peritubular Cells Involve the Cation Channel TRPV2
by Katja Eubler, Carola Herrmann, Astrid Tiefenbacher, Frank-Michael Köhn, J. Ullrich Schwarzer, Lars Kunz and Artur Mayerhofer
Int. J. Mol. Sci. 2018, 19(9), 2829; https://doi.org/10.3390/ijms19092829 - 19 Sep 2018
Cited by 16 | Viewed by 3932
Abstract
Peritubular cells are part of the wall of seminiferous tubules in the human testis and their contractile abilities are important for sperm transport. In addition, they have immunological roles. A proteomic analysis of isolated human testicular peritubular cells (HTPCs) revealed expression of the [...] Read more.
Peritubular cells are part of the wall of seminiferous tubules in the human testis and their contractile abilities are important for sperm transport. In addition, they have immunological roles. A proteomic analysis of isolated human testicular peritubular cells (HTPCs) revealed expression of the transient receptor potential channel subfamily V member 2 (TRPV2). This cation channel is linked to mechano-sensation and to immunological processes and inflammation in other organs. We verified expression of TRPV2 in peritubular cells in human sections by immunohistochemistry. It was also found in other testicular cells, including Sertoli cells and interstitial cells. In cultured HTPCs, application of cannabidiol (CBD), a known TRPV2 agonist, acutely induced a transient increase in intracellular Ca2+ levels. These Ca2+ transients could be blocked both by ruthenium red, an unspecific Ca2+ channel blocker, and tranilast (TRA), an antagonist of TRPV2, and were also abolished when extracellular Ca2+ was removed. Taken together this indicates functional TRPV2 channels in peritubular cells. When applied for 24 to 48 h, CBD induced expression of proinflammatory factors. In particular, mRNA and secreted protein levels of the proinflammatory chemokine interleukin-8 (IL-8/CXCL8) were elevated. Via its known roles as a major mediator of the inflammatory response and as an angiogenic factor, this chemokine may play a role in testicular physiology and pathology. Full article
(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling)
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13 pages, 1590 KiB  
Article
Mechanisms of PKA-Dependent Potentiation of Kv7.5 Channel Activity in Human Airway Smooth Muscle Cells
by Lyubov I. Brueggemann, Leanne L. Cribbs, Jeffrey Schwartz, Minhua Wang, Ahmed Kouta and Kenneth L. Byron
Int. J. Mol. Sci. 2018, 19(8), 2223; https://doi.org/10.3390/ijms19082223 - 30 Jul 2018
Cited by 12 | Viewed by 3027
Abstract
β-adrenergic receptor (βAR) activation promotes relaxation of both vascular and airway smooth muscle cells (VSMCs and ASMCs, respectively), though the signaling mechanisms have not been fully elucidated. We previously found that the activity of Kv7.5 voltage-activated potassium channels in VSMCs is robustly enhanced [...] Read more.
β-adrenergic receptor (βAR) activation promotes relaxation of both vascular and airway smooth muscle cells (VSMCs and ASMCs, respectively), though the signaling mechanisms have not been fully elucidated. We previously found that the activity of Kv7.5 voltage-activated potassium channels in VSMCs is robustly enhanced by activation of βARs via a mechanism involving protein kinase A (PKA)-dependent phosphorylation. We also found that enhancement of Kv7 channel activity in ASMCs promotes airway relaxation. Here we provide evidence that Kv7.5 channels are natively expressed in primary cultures of human ASMCs and that they conduct currents which are robustly enhanced in response to activation of the βAR/cyclic adenosine monophosphate (cAMP)/PKA pathway. MIT Scansite software analysis of putative PKA phosphorylation sites on Kv7.5 identified 8 candidate serine or threonine residues. Each residue was individually mutated to an alanine to prevent its phosphorylation and then tested for responses to βAR activation or to stimuli that elevate cAMP levels. Only the mutation of serine 53 (S53A), located on the amino terminus of Kv7.5, significantly reduced the increase in Kv7.5 current in response to these stimuli. A phospho-mimic mutation (S53D) exhibited characteristics of βAR-activated Kv7.5. Serine-to-alanine mutations of 6 putative PKA phosphorylation sites on the Kv7.5 C-terminus, individually or in combination, did not significantly reduce the enhancement of the currents in response to forskolin treatment (to elevate cAMP levels). We conclude that phosphorylation of S53 on the amino terminus of Kv7.5 is essential for PKA-dependent enhancement of channel activity in response to βAR activation in vascular and airway smooth muscle cells. Full article
(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling)
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17 pages, 3356 KiB  
Article
Involvement of Allosteric Effect and KCa Channels in Crosstalk between β2-Adrenergic and Muscarinic M2 Receptors in Airway Smooth Muscle
by Hiroaki Kume, Osamu Nishiyama, Takaaki Isoya, Yuji Higashimoto, Yuji Tohda and Yukihiro Noda
Int. J. Mol. Sci. 2018, 19(7), 1999; https://doi.org/10.3390/ijms19071999 - 09 Jul 2018
Cited by 9 | Viewed by 9191
Abstract
To advance the development of bronchodilators for asthma and chronic obstructive pulmonary disease (COPD), this study was designed to investigate the mechanism of functional antagonism between β2-adrenergic and muscarinic M2 receptors, focusing on allosteric effects and G proteins/ion channels coupling. [...] Read more.
To advance the development of bronchodilators for asthma and chronic obstructive pulmonary disease (COPD), this study was designed to investigate the mechanism of functional antagonism between β2-adrenergic and muscarinic M2 receptors, focusing on allosteric effects and G proteins/ion channels coupling. Muscarinic receptor antagonists (tiotropium, glycopyrronium, atropine) synergistically enhanced the relaxant effects of β2-adrenergic receptor agonists (procaterol, salbutamol, formoterol) in guinea pig trachealis. This crosstalk was inhibited by iberitoxin, a large-conductance Ca2+-activated K+ (KCa) channel inhibitor, whereas it was increased by verapamil, a L-type voltage-dependent Ca2+ (VDC) channel inhibitor; additionally, it was enhanced after tissues were incubated with pertussis or cholera toxin. This synergism converges in the G proteins (Gi, Gs)/KCa channel/VDC channel linkages. Muscarinic receptor antagonists competitively suppressed, whereas, β2-adrenergic receptor agonists noncompetitively suppressed muscarinic contraction. In concentration-inhibition curves for β2-adrenergic receptor agonists with muscarinic receptor antagonists, EC50 was markedly decreased, and maximal inhibition was markedly increased. Hence, muscarinic receptor antagonists do not bind to allosteric sites on muscarinic receptors. β2-Adrenergic receptor agonists bind to allosteric sites on these receptors; their intrinsic efficacy is attenuated by allosteric modulation (partial agonism). Muscarinic receptor antagonists enhance affinity and efficacy of β2-adrenergic action via allosteric sites in β2-adrenergic receptors (synergism). In conclusion, KCa channels and allosterism may be novel targets of bronchodilator therapy for diseases such as asthma and COPD. Full article
(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling)
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11 pages, 1532 KiB  
Article
PIEZO1 Channel Is a Potential Regulator of Synovial Sarcoma Cell-Viability
by Takahisa Suzuki, Yukiko Muraki, Noriyuki Hatano, Hiroka Suzuki and Katsuhiko Muraki
Int. J. Mol. Sci. 2018, 19(5), 1452; https://doi.org/10.3390/ijms19051452 - 14 May 2018
Cited by 27 | Viewed by 5167
Abstract
Detection of mechanical stress is essential for diverse biological functions including touch, audition, and maintenance of vascular myogenic tone. PIEZO1, a mechano-sensing cation channel, is widely expressed in neuronal and non-neuronal cells and is expected to be involved in important biological functions. Here, [...] Read more.
Detection of mechanical stress is essential for diverse biological functions including touch, audition, and maintenance of vascular myogenic tone. PIEZO1, a mechano-sensing cation channel, is widely expressed in neuronal and non-neuronal cells and is expected to be involved in important biological functions. Here, we examined the possibility that PIEZO1 is involved in the regulation of synovial sarcoma cell-viability. Application of a PIEZO1 agonist Yoda1 effectively induced Ca2+ response and cation channel currents in PIEZO1-expressing HEK (HEK-Piezo1) cells and synovial sarcoma SW982 (SW982) cells. Mechanical stress, as well as Yoda1, induced the activity of an identical channel of conductance with 21.6 pS in HEK-Piezo1 cells. In contrast, Yoda1 up to 10 μM had no effects on membrane currents in HEK cells without transfecting PIEZO1. A knockdown of PIEZO1 with siRNA in SW982 cells abolished Yoda1-induced Ca2+ response and significantly reduced cell cell-viability. Because PIEZO1 is highly expressed in SW982 cells and its knockdown affects cell-viability, this gene is a potential target against synovial sarcoma. Full article
(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling)
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14 pages, 4257 KiB  
Article
Effects of Nitric Oxide on Voltage-Gated K+ Currents in Human Cardiac Fibroblasts through the Protein Kinase G and Protein Kinase A Pathways but Not through S-Nitrosylation
by Hyemi Bae, Jeongyoon Choi, Young-Won Kim, Donghee Lee, Jung-Ha Kim, Jae-Hong Ko, Hyoweon Bang, Taeho Kim and Inja Lim
Int. J. Mol. Sci. 2018, 19(3), 814; https://doi.org/10.3390/ijms19030814 - 12 Mar 2018
Cited by 6 | Viewed by 3779
Abstract
This study investigated the expression of voltage-gated K+ (KV) channels in human cardiac fibroblasts (HCFs), and the effect of nitric oxide (NO) on the KV currents, and the underlying phosphorylation mechanisms. In reverse transcription polymerase chain reaction, two types [...] Read more.
This study investigated the expression of voltage-gated K+ (KV) channels in human cardiac fibroblasts (HCFs), and the effect of nitric oxide (NO) on the KV currents, and the underlying phosphorylation mechanisms. In reverse transcription polymerase chain reaction, two types of KV channels were detected in HCFs: delayed rectifier K+ channel and transient outward K+ channel. In whole-cell patch-clamp technique, delayed rectifier K+ current (IK) exhibited fast activation and slow inactivation, while transient outward K+ current (Ito) showed fast activation and inactivation kinetics. Both currents were blocked by 4-aminopyridine. An NO donor, S-nitroso-N-acetylpenicillamine (SNAP), increased the amplitude of IK in a concentration-dependent manner with an EC50 value of 26.4 µM, but did not affect Ito. The stimulating effect of SNAP on IK was blocked by pretreatment with 1H-(1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or by KT5823. 8-bromo-cyclic GMP stimulated the IK. The stimulating effect of SNAP on IK was also blocked by pretreatment with KT5720 or by SQ22536. Forskolin and 8-bromo-cyclic AMP each stimulated IK. On the other hand, the stimulating effect of SNAP on IK was not blocked by pretreatment of N-ethylmaleimide or by DL-dithiothreitol. Our data suggest that NO enhances IK, but not Ito, among KV currents of HCFs, and the stimulating effect of NO on IK is through the PKG and PKA pathways, not through S-nitrosylation. Full article
(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling)
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Review

Jump to: Research

19 pages, 752 KiB  
Review
Voltage-Dependent Sarcolemmal Ion Channel Abnormalities in the Dystrophin-Deficient Heart
by Xaver Koenig, Janine Ebner and Karlheinz Hilber
Int. J. Mol. Sci. 2018, 19(11), 3296; https://doi.org/10.3390/ijms19113296 - 23 Oct 2018
Cited by 10 | Viewed by 3695
Abstract
Mutations in the gene encoding for the intracellular protein dystrophin cause severe forms of muscular dystrophy. These so-called dystrophinopathies are characterized by skeletal muscle weakness and degeneration. Dystrophin deficiency also gives rise to considerable complications in the heart, including cardiomyopathy development and arrhythmias. [...] Read more.
Mutations in the gene encoding for the intracellular protein dystrophin cause severe forms of muscular dystrophy. These so-called dystrophinopathies are characterized by skeletal muscle weakness and degeneration. Dystrophin deficiency also gives rise to considerable complications in the heart, including cardiomyopathy development and arrhythmias. The current understanding of the pathomechanisms in the dystrophic heart is limited, but there is growing evidence that dysfunctional voltage-dependent ion channels in dystrophin-deficient cardiomyocytes play a significant role. Herein, we summarize the current knowledge about abnormalities in voltage-dependent sarcolemmal ion channel properties in the dystrophic heart, and discuss the potentially underlying mechanisms, as well as their pathophysiological relevance. Full article
(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling)
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20 pages, 1736 KiB  
Review
Gas Signaling Molecules and Mitochondrial Potassium Channels
by Agnieszka Walewska, Adam Szewczyk and Piotr Koprowski
Int. J. Mol. Sci. 2018, 19(10), 3227; https://doi.org/10.3390/ijms19103227 - 18 Oct 2018
Cited by 35 | Viewed by 5793
Abstract
Recently, gaseous signaling molecules, such as carbon monoxide (CO), nitric oxide (NO), and hydrogen sulfide (H2S), which were previously considered to be highly toxic, have been of increasing interest due to their beneficial effects at low concentrations. These so-called gasotransmitters affect [...] Read more.
Recently, gaseous signaling molecules, such as carbon monoxide (CO), nitric oxide (NO), and hydrogen sulfide (H2S), which were previously considered to be highly toxic, have been of increasing interest due to their beneficial effects at low concentrations. These so-called gasotransmitters affect many cellular processes, such as apoptosis, proliferation, cytoprotection, oxygen sensing, ATP synthesis, and cellular respiration. It is thought that mitochondria, specifically their respiratory complexes, constitute an important target for these gases. On the other hand, increasing evidence of a cytoprotective role for mitochondrial potassium channels provides motivation for the analysis of the role of gasotransmitters in the regulation of channel function. A number of potassium channels have been shown to exhibit activity within the inner mitochondrial membrane, including ATP-sensitive potassium channels, Ca2+-activated potassium channels, voltage-gated Kv potassium channels, and TWIK-related acid-sensitive K+ channel 3 (TASK-3). The effects of these channels include the regulation of mitochondrial respiration and membrane potential. Additionally, they may modulate the synthesis of reactive oxygen species within mitochondria. The opening of mitochondrial potassium channels is believed to induce cytoprotection, while channel inhibition may facilitate cell death. The molecular mechanisms underlying the action of gasotransmitters are complex. In this review, we focus on the molecular mechanisms underlying the action of H2S, NO, and CO on potassium channels present within mitochondria. Full article
(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling)
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25 pages, 506 KiB  
Review
Targeting Mitochondrial Ion Channels to Fight Cancer
by Magdalena Bachmann, Roberto Costa, Roberta Peruzzo, Elena Prosdocimi, Vanessa Checchetto and Luigi Leanza
Int. J. Mol. Sci. 2018, 19(7), 2060; https://doi.org/10.3390/ijms19072060 - 15 Jul 2018
Cited by 19 | Viewed by 5568
Abstract
In recent years, several experimental evidences have underlined a new role of ion channels in cancer development and progression. In particular, mitochondrial ion channels are arising as new oncological targets, since it has been proved that most of them show an altered expression [...] Read more.
In recent years, several experimental evidences have underlined a new role of ion channels in cancer development and progression. In particular, mitochondrial ion channels are arising as new oncological targets, since it has been proved that most of them show an altered expression during tumor development and the pharmacological targeting of some of them have been demonstrated to be able to modulate cancer growth and progression, both in vitro as well as in vivo in pre-clinical mouse models. In this scenario, pharmacology of mitochondrial ion channels would be in the near future a new frontier for the treatment of tumors. In this review, we discuss the new advances in the field, by focusing our attention on the improvements in new drug developments to target mitochondrial ion channels. Full article
(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling)
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13 pages, 1741 KiB  
Review
Calcium-Activated Cl Channel: Insights on the Molecular Identity in Epithelial Tissues
by Trey S. Rottgen, Andrew J. Nickerson and Vazhaikkurichi M. Rajendran
Int. J. Mol. Sci. 2018, 19(5), 1432; https://doi.org/10.3390/ijms19051432 - 10 May 2018
Cited by 8 | Viewed by 4021
Abstract
Calcium-activated chloride secretion in epithelial tissues has been described for many years. However, the molecular identity of the channel responsible for the Ca2+-activated Cl secretion in epithelial tissues has remained a mystery. More recently, TMEM16A has been identified as a [...] Read more.
Calcium-activated chloride secretion in epithelial tissues has been described for many years. However, the molecular identity of the channel responsible for the Ca2+-activated Cl secretion in epithelial tissues has remained a mystery. More recently, TMEM16A has been identified as a new putative Ca2+-activated Cl channel (CaCC). The primary goal of this article will be to review the characterization of TMEM16A, as it relates to the physical structure of the channel, as well as important residues that confer voltage and Ca2+-sensitivity of the channel. This review will also discuss the role of TMEM16A in epithelial physiology and potential associated-pathophysiology. This will include discussion of developed knockout models that have provided much needed insight on the functional localization of TMEM16A in several epithelial tissues. Finally, this review will examine the implications of the identification of TMEM16A as it pertains to potential novel therapies in several pathologies. Full article
(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling)
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3450 KiB  
Review
Primary Cilium-Dependent Signaling Mechanisms
by Rajasekharreddy Pala, Nedaa Alomari and Surya M. Nauli
Int. J. Mol. Sci. 2017, 18(11), 2272; https://doi.org/10.3390/ijms18112272 - 28 Oct 2017
Cited by 123 | Viewed by 18558
Abstract
Primary cilia are hair-like organelles and play crucial roles in vertebrate development, organogenesis, health, and many genetic disorders. A primary cilium is a mechano-sensory organelle that responds to mechanical stimuli in the micro-environment. A cilium is also a chemosensor that senses chemical signals [...] Read more.
Primary cilia are hair-like organelles and play crucial roles in vertebrate development, organogenesis, health, and many genetic disorders. A primary cilium is a mechano-sensory organelle that responds to mechanical stimuli in the micro-environment. A cilium is also a chemosensor that senses chemical signals surrounding a cell. The overall function of a cilium is therefore to act as a communication hub to transfer extracellular signals into intracellular responses. Although intracellular calcium has been one of the most studied signaling messengers that transmit extracellular signals into the cells, calcium signaling by various ion channels remains a topic of interest in the field. This may be due to a broad spectrum of cilia functions that are dependent on or independent of utilizing calcium as a second messenger. We therefore revisit and discuss the calcium-dependent and calcium-independent ciliary signaling pathways of Hedgehog, Wnt, PDGFR, Notch, TGF-β, mTOR, OFD1 autophagy, and other GPCR-associated signaling. All of these signaling pathways play crucial roles in various cellular processes, such as in organ and embryonic development, cardiac functioning, planar cell polarity, transactivation, differentiation, the cell cycle, apoptosis, tissue homeostasis, and the immune response. Full article
(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling)
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