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Ion Conductance and Ion Regulation in Human Health and Disease
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Ion Conductance and Ion Regulation in Human Health and Disease

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

Deadline for manuscript submissions: 30 August 2024 | Viewed by 3330

Special Issue Editor

Prof. Dr. Lars Kaestner

E-Mail Website
Guest Editor
Theoretical Medicine and Biosciences, Saarland University, Saarbruecken, Germany
Interests: red blood cells; ion channels; calcium signaling; microscopy; hematology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The gradients in ion concentration across the cell membrane are associated with many processes that define life. Therefore, the knowledge of ion conductance and ion regulation is vital to understanding cellular physiology and pathophysiology. This Special Issue deals with structures and functions of ion transport across membranes, with ion regulation based on intracellular ion stores and signaling processes involving ion transport. It includes studies of excitable cells but also covers non-excitable cells. Studies on model cells and cell lines as well as primary cells and tissue are welcome. This Special Issue covers original research and comprehensive reviews.

Since IJMS is a journal of molecular science, pure clinical studies will not be suitable for this Special Issue; however, clinical submissions with biomolecular experiments are welcome.

Prof. Dr. Lars Kaestner
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • ion channels
  • membrane potential
  • action potential
  • ion pumps
  • uniporter
  • co-transporter
  • patch-clamp
  • ion flux
  • concentration gradient
  • ion stores

Published Papers (4 papers)

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Research

19 pages, 3625 KiB  
Article
Investigating the Impact of Electrostatic Interactions on Calmodulin Binding and Ca2+-Dependent Activation of the Calcium-Gated Potassium SK4 Channel
by Émilie Segura, Juan Zhao, Marlena Broszczak, Frédéric Audet, Rémy Sauvé and Lucie Parent
Int. J. Mol. Sci. 2024, 25(8), 4255; https://doi.org/10.3390/ijms25084255 - 11 Apr 2024
Viewed by 425
Abstract
Ca2+ binding to the ubiquitous Ca2+ sensing protein calmodulin (CaM) activates the intermediate conductance Ca2+-activated SK4 channel. Potential hydrophilic pockets for CaM binding have been identified at the intracellular HA and HB helices in the C-terminal of SK4 from [...] Read more.
Ca2+ binding to the ubiquitous Ca2+ sensing protein calmodulin (CaM) activates the intermediate conductance Ca2+-activated SK4 channel. Potential hydrophilic pockets for CaM binding have been identified at the intracellular HA and HB helices in the C-terminal of SK4 from the three published cryo-EM structures of SK4. Single charge reversal substitutions at either site, significantly weakened the pull-down of SK4 by CaM wild-type (CaM), and decreased the TRAM-34 sensitive outward K+ current densities in native HEK293T cells when compared with SK4 WT measured under the same conditions. Only the doubly substituted SK4 R352D/R355D (HB helix) obliterated the CaM-mediated pull-down and thwarted outward K+ currents. However, overexpression of CaM E84K/E87K, which had been predicted to face the arginine doublet, restored the CaM-mediated pull-down of SK4 R352D/R355D and normalized its whole-cell current density. Virtual analysis of the putative salt bridges supports a unique role for the positively charged arginine doublet at the HB helix into anchoring the interaction with the negatively charged CaM glutamate 84 and 87 CaM. Our findings underscore the unique contribution of electrostatic interactions in carrying CaM binding onto SK4 and support the role of the C-terminal HB helix to the Ca2+-dependent gating process. Full article
(This article belongs to the Special Issue Ion Conductance and Ion Regulation in Human Health and Disease)
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20 pages, 2783 KiB  
Article
MLe-KCNQ2: An Artificial Intelligence Model for the Prognosis of Missense KCNQ2 Gene Variants
by Alba Saez-Matia, Markel G. Ibarluzea, Sara M-Alicante, Arantza Muguruza-Montero, Eider Nuñez, Rafael Ramis, Oscar R. Ballesteros, Diego Lasa-Goicuria, Carmen Fons, Mónica Gallego, Oscar Casis, Aritz Leonardo, Aitor Bergara and Alvaro Villarroel
Int. J. Mol. Sci. 2024, 25(5), 2910; https://doi.org/10.3390/ijms25052910 - 02 Mar 2024
Viewed by 841
Abstract
Despite the increasing availability of genomic data and enhanced data analysis procedures, predicting the severity of associated diseases remains elusive in the absence of clinical descriptors. To address this challenge, we have focused on the KV7.2 voltage-gated potassium channel gene ( [...] Read more.
Despite the increasing availability of genomic data and enhanced data analysis procedures, predicting the severity of associated diseases remains elusive in the absence of clinical descriptors. To address this challenge, we have focused on the KV7.2 voltage-gated potassium channel gene (KCNQ2), known for its link to developmental delays and various epilepsies, including self-limited benign familial neonatal epilepsy and epileptic encephalopathy. Genome-wide tools often exhibit a tendency to overestimate deleterious mutations, frequently overlooking tolerated variants, and lack the capacity to discriminate variant severity. This study introduces a novel approach by evaluating multiple machine learning (ML) protocols and descriptors. The combination of genomic information with a novel Variant Frequency Index (VFI) builds a robust foundation for constructing reliable gene-specific ML models. The ensemble model, MLe-KCNQ2, formed through logistic regression, support vector machine, random forest and gradient boosting algorithms, achieves specificity and sensitivity values surpassing 0.95 (AUC-ROC > 0.98). The ensemble MLe-KCNQ2 model also categorizes pathogenic mutations as benign or severe, with an area under the receiver operating characteristic curve (AUC-ROC) above 0.67. This study not only presents a transferable methodology for accurately classifying KCNQ2 missense variants, but also provides valuable insights for clinical counseling and aids in the determination of variant severity. The research context emphasizes the necessity of precise variant classification, especially for genes like KCNQ2, contributing to the broader understanding of gene-specific challenges in the field of genomic research. The MLe-KCNQ2 model stands as a promising tool for enhancing clinical decision making and prognosis in the realm of KCNQ2-related pathologies. Full article
(This article belongs to the Special Issue Ion Conductance and Ion Regulation in Human Health and Disease)
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8 pages, 1058 KiB  
Communication
Activity of Potassium Channels in CD8+ T Lymphocytes: Diagnostic and Prognostic Biomarker in Ovarian Cancer?
by Vivien Jusztus, Ghofrane Medyouni, Adrienn Bagosi, Rudolf Lampé, György Panyi, Orsolya Matolay, Eszter Maka, Zoárd Tibor Krasznai, Orsolya Vörös and Péter Hajdu
Int. J. Mol. Sci. 2024, 25(4), 1949; https://doi.org/10.3390/ijms25041949 - 06 Feb 2024
Viewed by 705
Abstract
CD8+ T cells play a role in the suppression of tumor growth and immunotherapy. Ion channels control the Ca2+-dependent function of CD8+ lymphocytes such as cytokine/granzyme production and tumor killing. Kv1.3 and KCa3.1 K+ channels stabilize the negative [...] Read more.
CD8+ T cells play a role in the suppression of tumor growth and immunotherapy. Ion channels control the Ca2+-dependent function of CD8+ lymphocytes such as cytokine/granzyme production and tumor killing. Kv1.3 and KCa3.1 K+ channels stabilize the negative membrane potential of T cells to maintain Ca2+ influx through CRAC channels. We assessed the expression of Kv1.3, KCa3.1 and CRAC in CD8+ cells from ovarian cancer (OC) patients (n = 7). We found that the expression level of Kv1.3 was higher in patients with malignant tumors than in control or benign tumor groups while the KCa3.1 activity was lower in the malignant tumor group as compared to the others. We demonstrated that the Ca2+ response in malignant tumor patients is higher compared to control groups. We propose that altered Kv1.3 and KCa3.1 expression in CD8+ cells in OC could be a reporter and may serve as a biomarker in diagnostics and that increased Ca2+ response through CRAC may contribute to the impaired CD8+ function. Full article
(This article belongs to the Special Issue Ion Conductance and Ion Regulation in Human Health and Disease)
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24 pages, 4246 KiB  
Article
The Gárdos Channel and Piezo1 Revisited: Comparison between Reticulocytes and Mature Red Blood Cells
by Polina Petkova-Kirova, Nicoletta Murciano, Giulia Iacono, Julia Jansen, Greta Simionato, Min Qiao, Carmen van der Zwaan, Maria Giustina Rotordam, Thomas John, Laura Hertz, Arjan J. Hoogendijk, Nadine Becker, Christian Wagner, Marieke von Lindern, Stephane Egee, Emile van den Akker and Lars Kaestner
Int. J. Mol. Sci. 2024, 25(3), 1416; https://doi.org/10.3390/ijms25031416 - 24 Jan 2024
Viewed by 844
Abstract
The Gárdos channel (KCNN4) and Piezo1 are the best-known ion channels in the red blood cell (RBC) membrane. Nevertheless, the quantitative electrophysiological behavior of RBCs and its heterogeneity are still not completely understood. Here, we use state-of-the-art biochemical methods to probe for the [...] Read more.
The Gárdos channel (KCNN4) and Piezo1 are the best-known ion channels in the red blood cell (RBC) membrane. Nevertheless, the quantitative electrophysiological behavior of RBCs and its heterogeneity are still not completely understood. Here, we use state-of-the-art biochemical methods to probe for the abundance of the channels in RBCs. Furthermore, we utilize automated patch clamp, based on planar chips, to compare the activity of the two channels in reticulocytes and mature RBCs. In addition to this characterization, we performed membrane potential measurements to demonstrate the effect of channel activity and interplay on the RBC properties. Both the Gárdos channel and Piezo1, albeit their average copy number of activatable channels per cell is in the single-digit range, can be detected through transcriptome analysis of reticulocytes. Proteomics analysis of reticulocytes and mature RBCs could only detect Piezo1 but not the Gárdos channel. Furthermore, they can be reliably measured in the whole-cell configuration of the patch clamp method. While for the Gárdos channel, the activity in terms of ion currents is higher in reticulocytes compared to mature RBCs, for Piezo1, the tendency is the opposite. While the interplay between Piezo1 and Gárdos channel cannot be followed using the patch clamp measurements, it could be proved based on membrane potential measurements in populations of intact RBCs. We discuss the Gárdos channel and Piezo1 abundance, interdependencies and interactions in the context of their proposed physiological and pathophysiological functions, which are the passing of small constrictions, e.g., in the spleen, and their active participation in blood clot formation and thrombosis. Full article
(This article belongs to the Special Issue Ion Conductance and Ion Regulation in Human Health and Disease)
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