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Biomolecules
Special Issues
Chloride Channels and Transporters in Health and Disease
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Chloride Channels and Transporters in Health and Disease

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 12031

Special Issue Editors

Dr. Paolo Scudieri

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Guest Editor
1. U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
2. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Università degli Studi di Genova, 16132 Genova, Italy
Interests: cystic fibrosis; epithelial physiology; airway physiology; TMEM16 genes; ion channel; phospholipid scramblases; in vitro models; neurodevelopmental disorders; induced pluripotent stem cells; brain organoids; therapeutic development; high content imaging; high throughput screening
Special Issues, Collections and Topics in MDPI journals
Dr. Ilaria Musante

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Guest Editor
DiNOGMI, Università di Genova, U.O.C. Genetica Medica, IRCSS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy
Interests: rare genetic diseases; neurodevelopmental disorders; cystic fibrosis; epithelial physiology; ion channels; metabotropic receptors; phospholipid scramblases; in vitro models; induced pluripotent stem cells; neuronal culture; brain organoids

Special Issue Information

Dear Colleagues,

Chloride is the most abundant anion in animal cells and chloride channels have fundamental role in physiology and disease. Chloride channels are indeed involved in a variety of biological functions, including trans-epithelial fluid secretion, cell volume regulation, cellular signaling, and vesicular trafficking and acidification. Different types of chloride channels have been identified, and many of them are implicated in severe human diseases. For example, CFTR (a cAMP-dependent anion channel) and CLC-1 (a voltage-gated chloride channel), which are the first two human chloride channels that have been cloned, are involved, as causative genes, in cystic fibrosis and myotonia congenita, respectively. In the last decade, many other chloride channels, regulated by calcium (for example TMEM16A), cell volume (LRRC8) or pH (TMEM206) have been identified and are now under deeply investigation to highlight their contributions to physiology, pathogenesis and as potential therapeutic targets in genetic diseases and cancer.

This Special Issue calls for original research, reviews, and perspectives that address the current knowledge in the field of chloride channels and transporters involved in human physiology and disease.

Dr. Paolo Scudieri
Dr. Ilaria Musante
Guest Editors

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Keywords

  • chloride channels
  • anionic transporters
  • calcium signaling
  • volume regulation
  • pH regulation
  • intracellular channels
  • electrophysiology
  • pharmacology
  • optogenetics
  • in vitro models
  • CRISPR/Cas9

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Published Papers (4 papers)

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Research

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18 pages, 8257 KiB  
Article
Impaired Autophagic Clearance with a Gain-of-Function Variant of the Lysosomal Cl−/H+ Exchanger ClC-7
by Shroddha Bose, Cecilia de Heus, Mary E. Kennedy, Fan Wang, Thomas J. Jentsch, Judith Klumperman and Tobias Stauber
Biomolecules 2023, 13(12), 1799; https://doi.org/10.3390/biom13121799 - 15 Dec 2023
Cited by 6 | Viewed by 2504
Abstract
ClC-7 is a ubiquitously expressed voltage-gated Cl−/H+ exchanger that critically contributes to lysosomal ion homeostasis. Together with its β-subunit Ostm1, ClC-7 localizes to lysosomes and to the ruffled border of osteoclasts, where it supports the acidification of the resorption lacuna. [...] Read more.
ClC-7 is a ubiquitously expressed voltage-gated Cl−/H+ exchanger that critically contributes to lysosomal ion homeostasis. Together with its β-subunit Ostm1, ClC-7 localizes to lysosomes and to the ruffled border of osteoclasts, where it supports the acidification of the resorption lacuna. Loss of ClC-7 or Ostm1 leads to osteopetrosis accompanied by accumulation of storage material in lysosomes and neurodegeneration. Interestingly, not all osteopetrosis-causing CLCN7 mutations from patients are associated with a loss of ion transport. Some rather result in an acceleration of voltage-dependent ClC-7 activation. Recently, a gain-of-function variant, ClC-7Y715C, that yields larger ion currents upon heterologous expression, was identified in two patients with neurodegeneration, organomegaly and albinism. However, neither the patients nor a mouse model that carried the equivalent mutation developed osteopetrosis, although expression of ClC-7Y715C induced the formation of enlarged intracellular vacuoles. Here, we investigated how, in transfected cells with mutant ClC-7, the substitution of this tyrosine impinged on the morphology and function of lysosomes. Combinations of the tyrosine mutation with mutations that either uncouple Cl− from H+ counter-transport or strongly diminish overall ion currents were used to show that increased ClC-7 Cl−/H+ exchange activity is required for the formation of enlarged vacuoles by membrane fusion. Degradation of endocytosed material was reduced in these compartments and resulted in an accumulation of lysosomal storage material. In cells expressing the ClC-7 gain-of-function mutant, autophagic clearance was largely impaired, resulting in a build-up of autophagic material. Full article
(This article belongs to the Special Issue Chloride Channels and Transporters in Health and Disease)
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15 pages, 4122 KiB  
Article
Cardioprotective Effect against Ischemia–Reperfusion Injury of PAK-200, a Dihydropyridine Analog with an Inhibitory Effect on Cl− but Not Ca2+ Current
by Iyuki Namekata, Miku Tamura, Jyunya Kase, Shogo Hamaguchi and Hikaru Tanaka
Biomolecules 2023, 13(12), 1719; https://doi.org/10.3390/biom13121719 - 29 Nov 2023
Viewed by 1383
Abstract
We examined the effects of a dihydropyridine analog, PAK-200, on guinea pig myocardium during experimental ischemia and reperfusion. In isolated ventricular cardiomyocytes, PAK-200 (1 μM) had no effect on the basal peak inward and steady-state currents but inhibited the isoprenaline-induced time-independent Cl− [...] Read more.
We examined the effects of a dihydropyridine analog, PAK-200, on guinea pig myocardium during experimental ischemia and reperfusion. In isolated ventricular cardiomyocytes, PAK-200 (1 μM) had no effect on the basal peak inward and steady-state currents but inhibited the isoprenaline-induced time-independent Cl− current. In the right atria, PAK-200 had no effect on the beating rate and the chronotropic response to isoprenaline. In an ischemia–reperfusion model with coronary-perfused right ventricular tissue, a decrease in contractile force and a rise in tension were observed during a period of 30-min no-flow ischemia. Upon reperfusion, contractile force returned to less than 50% of preischemic values. PAK-200 had no effect on the decline in contractile force during the no-flow ischemia but reduced the rise in resting tension. PAK-200 significantly improved the recovery of contractile force after reperfusion to about 70% of the preischemic value. PAK-200 was also shown to attenuate the decrease in tissue ATP during ischemia. Treatment of ventricular myocytes with an ischemia-mimetic solution resulted in depolarization of the mitochondrial membrane potential and an increase in cytoplasmic and mitochondrial Ca2+ concentrations. PAK-200 significantly delayed these changes. Thus, PAK-200 inhibits the cAMP-activated chloride current in cardiac muscle and may have protective effects against ischemia–reperfusion injury through novel mechanisms. Full article
(This article belongs to the Special Issue Chloride Channels and Transporters in Health and Disease)
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Review

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17 pages, 2741 KiB  
Review
Hypoxia, Ion Channels and Glioblastoma Malignancy
by Antonio Michelucci, Luigi Sforna, Fabio Franciolini and Luigi Catacuzzeno
Biomolecules 2023, 13(12), 1742; https://doi.org/10.3390/biom13121742 - 4 Dec 2023
Cited by 8 | Viewed by 2800
Abstract
The malignancy of glioblastoma (GBM), the most aggressive type of human brain tumor, strongly correlates with the presence of hypoxic areas within the tumor mass. Oxygen levels have been shown to control several critical aspects of tumor aggressiveness, such as migration/invasion and cell [...] Read more.
The malignancy of glioblastoma (GBM), the most aggressive type of human brain tumor, strongly correlates with the presence of hypoxic areas within the tumor mass. Oxygen levels have been shown to control several critical aspects of tumor aggressiveness, such as migration/invasion and cell death resistance, but the underlying mechanisms are still unclear. GBM cells express abundant K+ and Cl− channels, whose activity supports cell volume and membrane potential changes, critical for cell proliferation, migration and death. Volume-regulated anion channels (VRAC), which mediate the swelling-activated Cl− current, and the large-conductance Ca2+-activated K+ channels (BK) are both functionally upregulated in GBM cells, where they control different aspects underlying GBM malignancy/aggressiveness. The functional expression/activity of both VRAC and BK channels are under the control of the oxygen levels, and these regulations are involved in the hypoxia-induced GBM cell aggressiveness. The present review will provide a comprehensive overview of the literature supporting the role of these two channels in the hypoxia-mediated GBM malignancy, suggesting them as potential therapeutic targets in the treatment of GBM. Full article
(This article belongs to the Special Issue Chloride Channels and Transporters in Health and Disease)
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13 pages, 1858 KiB  
Review
SLC26A9 as a Potential Modifier and Therapeutic Target in Cystic Fibrosis Lung Disease
by Giulia Gorrieri, Federico Zara and Paolo Scudieri
Biomolecules 2022, 12(2), 202; https://doi.org/10.3390/biom12020202 - 25 Jan 2022
Cited by 5 | Viewed by 4437
Abstract
SLC26A9 belongs to the solute carrier family 26 (SLC26), which comprises membrane proteins involved in ion transport mechanisms. On the basis of different preliminary findings, including the phenotype of SlC26A9-deficient mice and its possible role as a gene modifier of the human phenotype [...] Read more.
SLC26A9 belongs to the solute carrier family 26 (SLC26), which comprises membrane proteins involved in ion transport mechanisms. On the basis of different preliminary findings, including the phenotype of SlC26A9-deficient mice and its possible role as a gene modifier of the human phenotype and treatment response, SLC26A9 has emerged as one of the most interesting alternative targets for the treatment of cystic fibrosis (CF). However, despite relevant clues, some open issues and controversies remain. The lack of specific pharmacological modulators, the elusive expression reported in the airways, and its complex relationships with CFTR and the CF phenotype prevent us from conclusively understanding the contribution of SLC26A9 in human lung physiology and its real potential as a therapeutic target in CF. In this review, we summarized the various studies dealing with SLC26A9 expression, molecular structure, and function as an anion channel or transporter; its interaction and functional relationships with CFTR; and its role as a gene modifier and tried to reconcile them in order to highlight the current understanding and the gap in knowledge regarding the contribution of SLC26A9 to human lung physiology and CF disease and treatment. Full article
(This article belongs to the Special Issue Chloride Channels and Transporters in Health and Disease)
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