scholarly journals Novel Roles for Chloride Channels, Exchangers, and Regulators in Chronic Inflammatory Airway Diseases

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Monica Sala-Rabanal ◽  
Zeynep Yurtsever ◽  
Kayla N. Berry ◽  
Tom J. Brett
Keyword(s):  
Chloride Channel ◽  
Chloride Channels ◽  
Mucociliary Clearance ◽  
Chloride Transport ◽  
Transport Proteins ◽  
Innate Immune ◽  
Mucus Secretion ◽  
Airway Constriction ◽  
Airway Diseases

Chloride transport proteins play critical roles in inflammatory airway diseases, contributing to the detrimental aspects of mucus overproduction, mucus secretion, and airway constriction. However, they also play crucial roles in contributing to the innate immune properties of mucus and mucociliary clearance. In this review, we focus on the emerging novel roles for a chloride channel regulator (CLCA1), a calcium-activated chloride channel (TMEM16A), and two chloride exchangers (SLC26A4/pendrin and SLC26A9) in chronic inflammatory airway diseases.

scholarly journals Chloride channels regulate differentiation and barrier functions of the mammalian airway

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Mu He ◽  
Bing Wu ◽  
Wenlei Ye ◽  
Daniel D Le ◽  
Adriane W Sinclair ◽  
...  
Keyword(s):  
Chloride Channels ◽  
Mucociliary Clearance ◽  
Mucosal Barrier ◽  
Barrier Dysfunction ◽  
Genetic Inactivation ◽  
Airway Diseases ◽  
Conducting Airway ◽  
Molecular Events ◽  
And Function ◽  
Human Fetal Development

The conducting airway forms a protective mucosal barrier and is the primary target of airway disorders. The molecular events required for the formation and function of the airway mucosal barrier, as well as the mechanisms by which barrier dysfunction leads to early onset airway diseases, remain unclear. In this study, we systematically characterized the developmental landscape of the mouse airway using single-cell RNA sequencing and identified remarkably conserved cellular programs operating during human fetal development. We demonstrated that in mouse, genetic inactivation of chloride channel Ano1/Tmem16a compromises airway barrier function, results in early signs of inflammation, and alters the airway cellular landscape by depleting epithelial progenitors. Mouse Ano1-/-mutants exhibited mucus obstruction and abnormal mucociliary clearance that resemble the airway defects associated with cystic fibrosis. The data reveal critical and non-redundant roles for Ano1 in organogenesis, and show that chloride channels are essential for mammalian airway formation and function.

ClC-5: ontogeny of an alternative chloride channel in respiratory epithelia

2002 ◽  
Vol 282 (3) ◽  
pp. L501-L507 ◽  
Author(s):  
Rebecca D. Edmonds ◽  
Ian V. Silva ◽  
William B. Guggino ◽  
Robert B. Butler ◽  
Pamela L. Zeitlin ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Chloride Channel ◽  
Chloride Channels ◽  
Chloride Transport ◽  
Premature Death ◽  
Fetal Lung ◽  
Chloride Secretion ◽  
Normal Lung ◽  
Ribonuclease Protection Assay

Chloride transport is critical to many functions of the lung. Molecular defects in the best-known chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR), lead to impaired function of airway defensins, hydration of airway surface fluid, and mucociliary clearance leading to chronic lung disease, and premature death, but do not cause defects in lung development. We examined the expression of one member of the ClC family of volume- and voltage-regulated channels using the ribonuclease protection assay and Western blot analysis in rats. ClC-5 mRNA and protein are most strongly expressed in the fetal lung, and expression is maintained although downregulated postnatally. In addition, using immunocytochemistry, we find that ClC-5 is predominantly expressed along the luminal surface of the airway epithelium, suggesting that ClC-5 may participate in lung chloride secretion. Identifying candidate genes for critical ion transport functions is essential for understanding normal lung morphogenesis and the pathophysiology of several lung diseases. In addition, the manipulation of non-CFTR chloride channels may provide a viable approach for treating cystic fibrosis lung disease.

In vivo role of CLC chloride channels in the kidney

2000 ◽  
Vol 279 (5) ◽  
pp. F802-F808 ◽  
Author(s):  
Shinichi Uchida
Keyword(s):  
Chloride Channel ◽  
Chloride Channels ◽  
Cellular Localization ◽  
Chloride Transport ◽  
Kidney Diseases ◽  
Cell Volume Regulation ◽  
Special Focus ◽  
Loss Of Function ◽  
Intracellular Vesicles

Chloride channels in the kidney are involved in important physiological functions such as cell volume regulation, acidification of intracellular vesicles, and transepithelial chloride transport. Among eight mammalian CLC chloride channels expressed in the kidney, three (CLC-K1, CLC-K2, and CLC-5) were identified to be related to kidney diseases in humans or mice. CLC-K1 mediates a transepithelial chloride transport in the thin ascending limb of Henle's loop and is essential for urinary concentrating mechanisms. CLC-K2 is a basolateral chloride channel in distal nephron segments and is necessary for chloride reabsorption. CLC-5 is a chloride channel in intracellular vesicles of proximal tubules and is involved in endocytosis. This review will cover the recent advances in research on the CLC chloride channels of the kidney with a special focus on the issues most necessary to understand their physiological roles in vivo, i.e., their intrarenal and cellular localization and their phenotypes of humans and mice that have their loss-of-function mutations.

scholarly journals Chloride transport modulators as drug candidates

2021 ◽  
Author(s):  
Alan S. Verkman ◽  
Luis J. V. Galietta
Keyword(s):  
Cystic Fibrosis ◽  
Drug Discovery ◽  
Small Molecule ◽  
Kidney Stones ◽  
Chloride Channel ◽  
Chloride Channels ◽  
Chloride Transport ◽  
Secretory Diarrhea ◽  
Small Molecule Modulators ◽  
Made In

Chloride transport across cell membranes is broadly involved in epithelial fluid transport, cell volume and pH regulation, muscle contraction, membrane excitability, and organellar acidification. The human genome encodes at least 53 chloride transporting proteins with expression in cell plasma or intracellular membranes, which include chloride channels, exchangers and cotransporters, some having broad anion specificity. Loss of function mutations in chloride transporters cause a wide variety of human diseases, including cystic fibrosis, secretory diarrhea, kidney stones, salt wasting nephropathy, myotonia, osteopetrosis, hearing loss and goiter. While impactful advances have been made in the past decade in drug treatment of cystic fibrosis using small molecule modulators of the defective cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, other chloride channels and solute carrier proteins (SLCs) represent relatively underexplored target classes for drug discovery. New opportunities have emerged for development of chloride transport modulators as potential therapeutics for secretory diarrheas, constipation, dry eye disorders, kidney stones, polycystic kidney disease, hypertension and osteoporosis. Approaches to chloride transport-targeted drug discovery are reviewed herein, with focus on chloride channel and exchanger classes in which recent preclinical advances have been made in the identification of small molecule modulators and in proof of concept testing in experimental animal models.

scholarly journals Epithelial chloride channel. Development of inhibitory ligands.

1987 ◽  
Vol 90 (6) ◽  
pp. 779-798 ◽  
Author(s):  
D W Landry ◽  
M Reitman ◽  
E J Cragoe ◽  
Q Al-Awqati
Keyword(s):  
Binding Site ◽  
Chloride Channel ◽  
Chloride Channels ◽  
Ethacrynic Acid ◽  
Apical Membrane ◽  
Chloride Transport ◽  
Membrane Vesicles ◽  
Kidney Cortex ◽  
High Affinity Binding Site ◽  
Apical Membrane Vesicles

Chloride channels are present in the majority of epithelial cells, where they mediate absorption or secretion of NaCl. Although the absorptive and secretory channels are well characterized in terms of their electrophysiological behavior, there is a lack of pharmacological ligands that can aid us in further functional and eventually molecular characterization. To obtain such ligands, we prepared membrane vesicles from bovine kidney cortex and apical membrane vesicles from trachea and found that they contain a chloride transport process that is electrically conductive. This conductance was reduced by preincubating the vesicles in media containing ATP or ATP-gamma-S, but not beta-methylene ATP, which suggests that the membranes contain a kinase that can close the channels. We then screened compounds derived from three classes: indanyloxyacetic acid (IAA), anthranilic acid (AA), and ethacrynic acid. We identified potent inhibitors from the IAA and the AA series. We tritiated IAA-94 and measured binding of this ligand to the kidney cortex membrane vesicles and found a high-affinity binding site whose dissociation constant (0.6 microM) was similar to the inhibition constant (1 microM). There was a good correlation between the inhibitory potency of several IAA derivatives and their efficacy in displacing [3H]IAA-94 from its binding site. Further, other chloride channel inhibitors, including AA derivatives, ethacrynic acid, bumetanide, and DIDS, also displaced the ligand from its binding site. A similar conductance was found in apical membrane vesicles from bovine trachea that was also inhibited by IAA-94 and AA-130B, but the inhibitory effects of these compounds were weaker than their effects on the renal cortex channel. The two drugs were also less potent in displacing [3H]IAA-94 from the tracheal binding site.

scholarly journals The Role of Serum Chloride in Acute and Chronic Heart Failure: A Narrative Review

2021 ◽  
Vol 11 (2) ◽  
pp. 87-98
Author(s):  
Frederick Berro Rivera ◽  
Pia Alfonso ◽  
Jem Marie Golbin ◽  
Kevin Lo ◽  
Edgar Lerma ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chloride Channel ◽  
Chloride Channels ◽  
Prognostic Value ◽  
Diuretic Therapy ◽  
Juxtaglomerular Apparatus ◽  
Sodium Chloride Cotransporter ◽  
Serum Chloride ◽  
And Function

Clinical guidelines include diuretics for the treatment of heart failure (HF), not to decrease mortality but to decrease symptoms and hospitalizations. More attention has been paid to the worse outcomes, including mortality, associated with continual diuretic therapy due to hypochloremia. Studies have revealed a pivotal role for serum chloride in the pathophysiology of HF and is now a target of treatment to decrease mortality. The prognostic value of serum chloride in HF has been the subject of much attention. Mechanistically, the macula densa, a region in the renal juxtaglomerular apparatus, relies on chloride levels to sense salt and volume status. The recent discovery of with-no-lysine (K) (WNK) protein kinase as an intracellular chloride sensor sheds light on the possible reason of diuretic resistance in HF. The action of chloride on WNKs results in the upregulation of the sodium-potassium-chloride cotransporter and sodium-chloride cotransporter receptors, which could lead to increased electrolyte and fluid reabsorption. Genetic studies have revealed that a variant of a voltage-sensitive chloride channel (CLCNKA) gene leads to almost a 50% decrease in current amplitude and function of the renal chloride channel. This variant increases the risk of HF. Several trials exploring the prognostic value of chloride in both acute and chronic HF have shown mostly positive results, some even suggesting a stronger role than sodium. However, so far, interventional trials exploring serum chloride as a therapeutic target have been largely inconclusive. This study is a review of the pathophysiologic effects of hypochloremia in HF, the genetics of chloride channels, and clinical trials that are underway to investigate novel approaches to HF management.

scholarly journals mtCLIC/CLIC4, an Organellular Chloride Channel Protein, Is Increased by DNA Damage and Participates in the Apoptotic Response to p53

2002 ◽  
Vol 22 (11) ◽  
pp. 3610-3620 ◽  
Author(s):  
Ester Fernández-Salas ◽  
Kwang S. Suh ◽  
Vladislav V. Speransky ◽  
Wendy L. Bowers ◽  
Joshua M. Levy ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chloride Channel ◽  
Chloride Channels ◽  
Mitochondrial Membrane ◽  
Cellular Response ◽  
Mitochondrial Protein ◽  
Inner Mitochondrial Membrane ◽  
Necrosis Factor Alpha ◽  
Channel Protein ◽  
Factor Alpha

ABSTRACT mtCLIC/CLIC4 (referred to here as mtCLIC) is a p53- and tumor necrosis factor alpha-regulated cytoplasmic and mitochondrial protein that belongs to the CLIC family of intracellular chloride channels. mtCLIC associates with the inner mitochondrial membrane. Dual regulation of mtCLIC by two stress response pathways suggested that this chloride channel protein might contribute to the cellular response to cytotoxic stimuli. DNA damage or overexpression of p53 upregulates mtCLIC and induces apoptosis. Overexpression of mtCLIC by transient transfection reduces mitochondrial membrane potential, releases cytochrome c into the cytoplasm, activates caspases, and induces apoptosis. mtCLIC is additive with Bax in inducing apoptosis without a physical association of the two proteins. Antisense mtCLIC prevents the increase in mtCLIC levels and reduces apoptosis induced by p53 but not apoptosis induced by Bax, suggesting that the two proapoptotic proteins function through independent pathways. Our studies indicate that mtCLIC, like Bax, Noxa, p53AIP1, and PUMA, participates in a stress-induced death pathway converging on mitochondria and should be considered a target for cancer therapy through genetic or pharmacologic approaches.

The Insecticide Avermectin Bla Activates A Chloride Channel in Crayfish Muscle Membrane

1989 ◽  
Vol 142 (1) ◽  
pp. 191-205
Author(s):  
F. ZUFALL ◽  
CH. FRANKE ◽  
H. HATT
Keyword(s):  
Chloride Channel ◽  
Chloride Channels ◽  
Single Channel ◽  
Chloride Concentration ◽  
Ibotenic Acid ◽  
Muscle Membrane ◽  
Stomach Muscle ◽  
Quisqualic Acid ◽  
Drug Actions ◽  
Inside Out

Effects of avermectin B1a (AVM) have been tested on excised outside-out or inside-out patches of crayfish stomach muscle membrane. Continuous supervision of AVM (0.1-1 pmoll−1) to the outside-out patches induced openings of channels (22 pS) which were similar in conductance and kinetics to the chloride channels activated by glutamate, quisqualic acid, ibotenic acid and nicotinic agonists, whereas GABA mainly activated a second, larger conductance state (44 pS). This effect was reversible. AVM did not activate the excitatory, glutamate-activated cation channel. Upon raising the AVM-concentration to 10 pmoll−1 and above, an enormous increase in the rate of openings of channels (22 pS) occurred. This effect could not be washed out during the lifetime of the patch. Using inside-out patches, it was shown that the single-channel current amplitude, for both the reversible and irreversible drug actions, strongly depended on intracellular chloride concentration. Applied to the sarcoplasmic side of inside-out patches, AVM did not activate any channel. The distribution of open times for 0.1 pmoll−1 AVM could be fitted by a single exponential (τ=3.3ms). For a higher AVM concentration (1 pmoll−1) two exponentials (τ1 = 0.5ms, τ2 = 2.4ms) were needed to fit the distribution. A similar effect was elicited by decreasing the extracellular Ca2+ concentration from 13.5 to 1 mmoll−1 during the application of 0.1 pmoll−1 AVM. Picrotoxin blocked the activation of chloride channels for both the reversible and irreversible effects of AVM. It is suggested that AVM activates the multitransmitter-gated chloride channel in this preparation. Binding sites for the drug are discussed.

scholarly journals Multiscale mechanics of mucociliary clearance in the lung

2019 ◽  
Vol 375 (1792) ◽  
pp. 20190160 ◽  
Author(s):  
Janna C. Nawroth ◽  
Anne M. van der Does ◽  
Amy Ryan (Firth) ◽  
Eva Kanso
Keyword(s):  
Cell Biology ◽  
Mucociliary Clearance ◽  
Treatment Options ◽  
Diagnostic Tools ◽  
Regional Variability ◽  
Multiscale Mechanics ◽  
Airway Diseases ◽  
Open Questions ◽  
Human Lungs ◽  
The Relationship

Mucociliary clearance (MCC) is one of the most important defence mechanisms of the human respiratory system. Its failure is implicated in many chronic and debilitating airway diseases. However, due to the complexity of lung organization, we currently lack full understanding on the relationship between these regional differences in anatomy and biology and MCC functioning. For example, it is unknown whether the regional variability of airway geometry, cell biology and ciliary mechanics play a functional role in MCC. It therefore remains unclear whether the regional preference seen in some airway diseases could originate from local MCC dysfunction. Though great insights have been gained into the genetic basis of cilia ultrastructural defects in airway ciliopathies, the scaling to regional MCC function and subsequent clinical phenotype remains unpredictable. Understanding the multiscale mechanics of MCC would help elucidate genotype–phenotype relationships and enable better diagnostic tools and treatment options. Here, we review the hierarchical and variable organization of ciliated airway epithelium in human lungs and discuss how this organization relates to MCC function. We then discuss the relevancy of these structure–function relationships to current topics in lung disease research. Finally, we examine how state-of-the-art computational approaches can help address existing open questions. This article is part of the Theo Murphy meeting issue ‘Unity and diversity of cilia in locomotion and transport’.

Homomeric RDL and Heteromeric RDL/LCCH3 GABA Receptors in the Honeybee Antennal Lobes: Two Candidates for Inhibitory Transmission in Olfactory Processing

2010 ◽  
Vol 103 (1) ◽  
pp. 458-468 ◽  
Author(s):  
Julien Pierre Dupuis ◽  
Michaël Bazelot ◽  
Guillaume Stéphane Barbara ◽  
Sandrine Paute ◽  
Monique Gauthier ◽  
...  
Keyword(s):  
Information Processing ◽  
Chloride Channel ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Chloride Channels ◽  
Physiological Role ◽  
Inhibitory Transmission ◽  
Olfactory Information ◽  
Whole Cell Patch Clamp ◽  
Inward Currents

γ-Aminobutyric acid (GABA)–gated chloride channel receptors are abundant in the CNS, where their physiological role is to mediate fast inhibitory neurotransmission. In insects, this inhibitory transmission plays a crucial role in olfactory information processing. In an effort to understand the nature and properties of the ionotropic receptors involved in these processes in the honeybee Apis mellifera, we performed a pharmacological and molecular characterization of GABA-gated channels in the primary olfactory neuropile of the honeybee brain—the antennal lobe (AL)—using whole cell patch-clamp recordings coupled with single-cell RT-PCR. Application of GABA onto AL cells at −110 mV elicited fast inward currents, demonstrating the existence of ionotropic GABA-gated chloride channels. Molecular analysis of the GABA-responding cells revealed that both subunits RDL and LCCH3 were expressed out of the three orthologs of Drosophila melanogaster GABA-receptor subunits encoded within the honeybee genome (RDL, resistant to dieldrin; GRD, GABA/glycine-like receptor of Drosophila ; LCCH3, ligand-gated chloride channel homologue 3), opening the door to possible homo- and/or heteromeric associations. The resulting receptors were activated by insect GABA-receptor agonists muscimol and CACA and blocked by antagonists fipronil, dieldrin, and picrotoxin, but not bicuculline, displaying a typical RDL-like pharmacology. Interestingly, increasing the intracellular calcium concentration potentiated GABA-elicited currents, suggesting a modulating effect of calcium on GABA receptors possibly through phosphorylation processes that remain to be determined. These results indicate that adult honeybee AL cells express typical RDL-like GABA receptors whose properties support a major role in synaptic inhibitory transmission during olfactory information processing.

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