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The Role of Ion-Transporting Proteins in Human Disease

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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: closed (30 September 2023) | Viewed by 14301

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Special Issue Editors

Prof. Dr. Yoshinori Marunaka

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Guest Editor

1. Medical Research Institute, Kyoto Industrial Health Association, Kyoto 604-8472, Japan
2. Research Organization of Science and Technology, Ritsumeikan University, Kusatsu 525-8577, Japan
3. Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 802-8566, Japan
Interests: diabetes mellitus; cancer; ion environments
Special Issues, Collections and Topics in MDPI journals

Dr. Marcelo A. Catalán

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Guest Editor

Instituto de Fisiologia, Facultad de Medicina, Universidad Austral de Chile, Valdivia 5090000, Chile
Interests: ion channels; ion transporters; solute transport; epithelial physiology; channelopaties; transportopathies

Special Issue Information

Dear Colleagues,

After the discovery of the CFTR gene and its most frequent mutation (ΔF508) causing cystic fibrosis (CF) in the late 1980s, many other genes encoding for ion-transporting channels or transporter proteins have been linked to human diseases. Even though the discovery of genes associated with human diseases is a great step forward in the field, the development of therapies for treating most such channelopathies and transportopathies have not been achieved.

Given the technological advancements made in cryogenic electron microscopy (cryo-EM), the structures of several ion channels and ion transporters involved in human diseases have been elucidated in the past few years. The availability of the protein structures should be associated with a significant advancement in the development of new rational therapies for treating defective ion-transport processes due to mutations in genes encoding for ion channels or transporters.

The present Special Issue aims to publish recent advances in the ion-transporting proteins associated with human diseases, with special emphasis on studies providing insights into the molecular mechanisms that cause channel or transporter dysfunction.

Original research and review articles are welcome in this Special Issue.

Prof. Dr. Yoshinori Marunaka
Dr. Marcelo A. Catalán
Guest Editors

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

plasma membrane
organelles
ion channels
ion transporters
gene mutations
channelopathy
transportopathy

Published Papers (7 papers)

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Editorial

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9 pages, 3273 KiB

Open AccessEditorial

The Role of Ion-Transporting Proteins in Human Disease

by Yoshinori Marunaka

Int. J. Mol. Sci. 2024, 25(3), 1726; https://doi.org/10.3390/ijms25031726 - 31 Jan 2024

Viewed by 616

Abstract

This Special Issue focuses on the significance of ion-transporting proteins, such as ion channels and transporters, providing evidence for their significant contribution to bodily and cellular functions via the regulation of signal transduction and ionic environments [...] Full article

(This article belongs to the Special Issue The Role of Ion-Transporting Proteins in Human Disease)

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Research

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13 pages, 3820 KiB

Open AccessArticle

K⁺-Driven Cl⁻/HCO₃⁻ Exchange Mediated by Slc4a8 and Slc4a10

by Gaspar Peña-Münzenmayer, Alvin T. George, Nuria Llontop, Yuliet Mazola, Natalia Apablaza, Carlos Spichiger, Sebastián Brauchi, José Sarmiento, Leandro Zúñiga, Wendy González and Marcelo A. Catalán

Int. J. Mol. Sci. 2024, 25(8), 4575; https://doi.org/10.3390/ijms25084575 - 22 Apr 2024

Viewed by 344

Abstract

Slc4a genes encode various types of transporters, including Na⁺-HCO₃⁻ cotransporters, Cl⁻/HCO₃⁻ exchangers, or Na⁺-driven Cl⁻/HCO₃⁻ exchangers. Previous research has revealed that Slc4a9 (Ae4) functions as a Cl⁻/HCO₃⁻ exchanger, which can be driven by either Na⁺ or K⁺, prompting investigation into whether other Slc4a members facilitate cation-dependent anion transport. In the present study, we show that either Na⁺ or K⁺ drive Cl⁻/HCO₃⁻ exchanger activity in cells overexpressing Slc4a8 or Slc4a10. Further characterization of cation-driven Cl⁻/HCO₃⁻ exchange demonstrated that Slc4a8 and Slc4a10 also mediate Cl⁻ and HCO₃⁻-dependent K⁺ transport. Full-atom molecular dynamics simulation on the recently solved structure of Slc4a8 supports the coordination of K⁺ at the Na⁺ binding site in S1. Sequence analysis shows that the critical residues coordinating monovalent cations are conserved among mouse Slc4a8 and Slc4a10 proteins. Together, our results suggest that Slc4a8 and Slc4a10 might transport K⁺ in the same direction as HCO₃⁻ ions in a similar fashion to that described for Na⁺ transport in the rat Slc4a8 structure. Full article

(This article belongs to the Special Issue The Role of Ion-Transporting Proteins in Human Disease)

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52 pages, 8456 KiB

Open AccessArticle

A Comparative Study on the Lysosomal Cation Channel TMEM175 Using Automated Whole-Cell Patch-Clamp, Lysosomal Patch-Clamp, and Solid Supported Membrane-Based Electrophysiology: Functional Characterization and High-Throughput Screening Assay Development

by Andre Bazzone, Maria Barthmes, Cecilia George, Nina Brinkwirth, Rocco Zerlotti, Valentin Prinz, Kim Cole, Søren Friis, Alexander Dickson, Simon Rice, Jongwon Lim, May Fern Toh, Milad Mohammadi, Davide Pau, David J. Stone, John J. Renger and Niels Fertig

Int. J. Mol. Sci. 2023, 24(16), 12788; https://doi.org/10.3390/ijms241612788 - 14 Aug 2023

Cited by 3 | Viewed by 2785

Abstract

The lysosomal cation channel TMEM175 is a Parkinson’s disease-related protein and a promising drug target. Unlike whole-cell automated patch-clamp (APC), lysosomal patch-clamp (LPC) facilitates physiological conditions, but is not yet suitable for high-throughput screening (HTS) applications. Here, we apply solid supported membrane-based electrophysiology (SSME), which enables both direct access to lysosomes and high-throughput electrophysiological recordings. In SSME, ion translocation mediated by TMEM175 is stimulated using a concentration gradient at a resting potential of 0 mV. The concentration-dependent K⁺ response exhibited an I/c curve with two distinct slopes, indicating the existence of two conducting states. We measured H⁺ fluxes with a permeability ratio of P_H/P_K = 48,500, which matches literature findings from patch-clamp studies, validating the SSME approach. Additionally, TMEM175 displayed a high pH dependence. Decreasing cytosolic pH inhibited both K⁺ and H⁺ conductivity of TMEM175. Conversely, lysosomal pH and pH gradients did not have major effects on TMEM175. Finally, we developed HTS assays for drug screening and evaluated tool compounds (4-AP, Zn as inhibitors; DCPIB, arachidonic acid, SC-79 as enhancers) using SSME and APC. Additionally, we recorded EC₅₀ data for eight blinded TMEM175 enhancers and compared the results across all three assay technologies, including LPC, discussing their advantages and disadvantages. Full article

(This article belongs to the Special Issue The Role of Ion-Transporting Proteins in Human Disease)

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16 pages, 4563 KiB

Open AccessArticle

Human Colonoid–Myofibroblast Coculture for Study of Apical Na⁺/H⁺ Exchangers of the Lower Cryptal Neck Region

by Azam Salari, Kunyan Zhou, Katerina Nikolovska, Ursula Seidler and Mahdi Amiri

Int. J. Mol. Sci. 2023, 24(5), 4266; https://doi.org/10.3390/ijms24054266 - 21 Feb 2023

Cited by 4 | Viewed by 1578

Abstract

Cation and anion transport in the colonocyte apical membrane is highly spatially organized along the cryptal axis. Because of lack of experimental accessibility, information about the functionality of ion transporters in the colonocyte apical membrane in the lower part of the crypt is scarce. The aim of this study was to establish an in vitro model of the colonic lower crypt compartment, which expresses the transit amplifying/progenitor (TA/PE) cells, with accessibility of the apical membrane for functional study of lower crypt-expressed Na⁺/H⁺ exchangers (NHEs). Colonic crypts and myofibroblasts were isolated from human transverse colonic biopsies, expanded as three-dimensional (3D) colonoids and myofibroblast monolayers, and characterized. Filter-grown colonic myofibroblast–colonic epithelial cell (CM-CE) cocultures (myofibroblasts on the bottom of the transwell and colonocytes on the filter) were established. The expression pattern for ion transport/junctional/stem cell markers of the CM-CE monolayers was compared with that of nondifferentiated (EM) and differentiated (DM) colonoid monolayers. Fluorometric pH_i measurements were performed to characterize apical NHEs. CM-CE cocultures displayed a rapid increase in transepithelial electrical resistance (TEER), paralleled by downregulation of claudin-2. They maintained proliferative activity and an expression pattern resembling TA/PE cells. The CM-CE monolayers displayed high apical Na⁺/H⁺ exchange activity, mediated to >80% by NHE2. Human colonoid–myofibroblast cocultures allow the study of ion transporters that are expressed in the apical membrane of the nondifferentiated colonocytes of the cryptal neck region. The NHE2 isoform is the predominant apical Na⁺/H⁺ exchanger in this epithelial compartment. Full article

(This article belongs to the Special Issue The Role of Ion-Transporting Proteins in Human Disease)

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23 pages, 8509 KiB

Open AccessArticle

Understanding the Role of ATP Release through Connexins Hemichannels during Neurulation

by Lina Mariana Tovar, Carlos Felipe Burgos, Gonzalo E. Yévenes, Gustavo Moraga-Cid, Jorge Fuentealba, Claudio Coddou, Luisa Bascunan-Godoy, Claudio Catrupay, Angel Torres and Patricio A. Castro

Int. J. Mol. Sci. 2023, 24(3), 2159; https://doi.org/10.3390/ijms24032159 - 21 Jan 2023

Cited by 3 | Viewed by 2012

Abstract

Neurulation is a crucial process in the formation of the central nervous system (CNS), which begins with the folding and fusion of the neural plate, leading to the generation of the neural tube and subsequent development of the brain and spinal cord. Environmental and genetic factors that interfere with the neurulation process promote neural tube defects (NTDs). Connexins (Cxs) are transmembrane proteins that form gap junctions (GJs) and hemichannels (HCs) in vertebrates, allowing cell-cell (GJ) or paracrine (HCs) communication through the release of ATP, glutamate, and NAD⁺; regulating processes such as cell migration and synaptic transmission. Changes in the state of phosphorylation and/or the intracellular redox potential activate the opening of HCs in different cell types. Cxs such as Cx43 and Cx32 have been associated with proliferation and migration at different stages of CNS development. Here, using molecular and cellular biology techniques (permeability), we demonstrate the expression and functionality of HCs-Cxs, including Cx46 and Cx32, which are associated with the release of ATP during the neurulation process in Xenopus laevis. Furthermore, applications of FGF2 and/or changes in intracellular redox potentials (DTT), well known HCs-Cxs modulators, transiently regulated the ATP release in our model. Importantly, the blockade of HCs-Cxs by carbenoxolone (CBX) and enoxolone (ENX) reduced ATP release with a concomitant formation of NTDs. We propose two possible and highly conserved binding sites (N and E) in Cx46 that may mediate the pharmacological effect of CBX and ENX on the formation of NTDs. In summary, our results highlight the importance of ATP release mediated by HCs-Cxs during neurulation. Full article

(This article belongs to the Special Issue The Role of Ion-Transporting Proteins in Human Disease)

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Review

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20 pages, 1224 KiB

Open AccessReview

Hypoxic Stress-Dependent Regulation of Na,K-ATPase in Ischemic Heart Disease

by Emel Baloglu

Int. J. Mol. Sci. 2023, 24(9), 7855; https://doi.org/10.3390/ijms24097855 - 26 Apr 2023

Cited by 5 | Viewed by 2844

Abstract

In cardiomyocytes, regular activity of the Na,K-ATPase (NKA) and its Na/K pump activity is essential for maintaining ion gradients, excitability, propagation of action potentials, electro-mechanical coupling, trans-membrane Na⁺ and Ca²⁺ gradients and, thus, contractility. The activity of NKA is impaired in ischemic heart disease and heart failure, which has been attributed to decreased expression of the NKA subunits. Decreased NKA activity leads to intracellular Na⁺ and Ca²⁺ overload, diastolic dysfunction and arrhythmias. One signal likely related to these events is hypoxia, where hypoxia-inducible factors (HIF) play a critical role in the adaptation of cells to low oxygen tension. HIF activity increases in ischemic heart, hypertension, heart failure and cardiac fibrosis; thus, it might contribute to the impaired function of NKA. This review will mainly focus on the regulation of NKA in ischemic heart disease in the context of stressed myocardium and the hypoxia–HIF axis and argue on possible consequences of treatment. Full article

(This article belongs to the Special Issue The Role of Ion-Transporting Proteins in Human Disease)

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50 pages, 2644 KiB

Open AccessReview

The Epithelial Sodium Channel—An Underestimated Drug Target

by Rosa Lemmens-Gruber and Susan Tzotzos

Int. J. Mol. Sci. 2023, 24(9), 7775; https://doi.org/10.3390/ijms24097775 - 24 Apr 2023

Cited by 6 | Viewed by 3257

Abstract

Epithelial sodium channels (ENaC) are part of a complex network of interacting biochemical pathways and as such are involved in several disease states. Dependent on site and type of mutation, gain- or loss-of-function generated symptoms occur which span from asymptomatic to life-threatening disorders such as Liddle syndrome, cystic fibrosis or generalized pseudohypoaldosteronism type 1. Variants of ENaC which are implicated in disease assist further understanding of their molecular mechanisms in order to create models for specific pharmacological targeting. Identification and characterization of ENaC modifiers not only furthers our basic understanding of how these regulatory processes interact, but also enables discovery of new therapeutic targets for the disease conditions caused by ENaC dysfunction. Numerous test compounds have revealed encouraging results in vitro and in animal models but less in clinical settings. The EMA- and FDA-designated orphan drug solnatide is currently being tested in phase 2 clinical trials in the setting of acute respiratory distress syndrome, and the NOX1/ NOX4 inhibitor setanaxib is undergoing clinical phase 2 and 3 trials for therapy of primary biliary cholangitis, liver stiffness, and carcinoma. The established ENaC blocker amiloride is mainly used as an add-on drug in the therapy of resistant hypertension and is being studied in ongoing clinical phase 3 and 4 trials for special applications. This review focuses on discussing some recent developments in the search for novel therapeutic agents. Full article

(This article belongs to the Special Issue The Role of Ion-Transporting Proteins in Human Disease)

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