Chloride channel opener

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Chloride channel openers refer to a specific category of drugs designed to modulate chloride channels in the human body. Chloride channels are anion-selective channels which are involved in a wide variety of physiological functions and processes such as the regulation of neuroexcitation, transepithelial salt transport, and smooth muscle contraction. [1] Due to their distribution throughout the body, diversity, functionality, and associated pathology, chloride channels [2] represent an ideal target for the development of channel modulating drugs such as chloride channel openers.

Contents

Chloride channel modulators include chloride channel openers, and chloride channel blockers, both of which modulate the transport of chloride ions through chloride channels. [3] Chloride channel openers specifically work by either preventing the closure of chloride channels, or promoting their opening, thus helping to facilitate movement of chloride ions into a cell.

In general, mutations in various chloride channels throughout the human body can result in many pathologies, such as macular degeneration, myotonia, cystic fibrosis, and hyperekplexia. [3] Chloride channel openers have been proposed to treat a variety of such pathologies, most notably including cystic fibrosis, a genetic disorder in which a defect in the cystic fibrosis transmembrane conductance regulator protein impacts chloride ion transport across epithelial cells. [4]

Chloride channels remain a somewhat under-explored target for drug development despite their biological significance, due to various issues associated with the development of successful chloride channel drugs. As a result, the development of chloride channel modulators such as chloride channel opening drugs has been limited. The relative structural complexity of chloride channels, their varied roles in biological processes, and the problems associated with the development of drugs with high specificity emphasize the necessity for further research in this area.

Chloride Channels

Ion Channels

Ion channels are pore-forming proteins which help facilitate the transport of ions across membranes, typically plasma membranes or the membranes of organelles within cells [5] [14]. They are considered to be the second largest drug target for existing drugs, after G protein-coupled receptors. [5] There is a wide variety of ion channels, and they are typically characterized by their gating mechanism, such as ligand-gated channels or voltage-gated channels, and the ion being transported, such as sodium (Na), potassium (K), or chloride (Cl) ions. [5]

Voltage-gated ion channels

Several different intracellular transport channels, with varying functions, exist throughout the human body to facilitate routine upkeep and maintenance. [6] Such transport channels, including ligand gated and voltage gated channels, regulate uptake of chemical stimulants that trigger neuronal function. [7] Chloride (Cl-), the most abundant anion in the human body, [6] [7] as well as Sodium (Na+) and Potassium (K+), determine the electrochemical potential across a cell. [6] The difference in concentration of chloride determines if a cell will depolarize or hyperpolarize the plasma membrane, resulting in a neural response. [6] Chloride channels are a type of voltage-gated ion channel, and are responsible for regulating chloride ion transport and therefore neural excitation or inhibition. [7]

Physiological significance of chloride ion channels

Chloride channels are present throughout the body and have important roles in many physiological processes. Some functions of chloride channels include ion homeostasis, cell volume regulation, and modulation of electrical excitability. [8] In the central nervous system (CNS), chloride channels are responsible for both direct modulation of neuronal activity and indirect control of neuronal functions through release of gliotransmitters by astrocytes through gating of organic anions such as GABA. [7] Chloride channels also partake in cell apoptosis caused by endoplasmic reticulum (ER) stress, in addition to their roles in modulation of membrane potential and gating anions. [7] ER stress notably plays a role in neurological disorders such as Alzheimer’s (AD).

Chloride ion transport

Chloride ions stimulate chloride channels to open, and so the active and efficient transport of chloride ions is crucial to neural function. Chloride is transported across necessary cell membranes via chloride transporting proteins. [7] The function of these proteins is crucial for appropriate neural pathology and dysfunction of these proteins is characteristic of diseases and disorders such as epilepsy and autism. [7]

Gene families of chloride channels

Although opinions vary among experts regarding classification of the different chloride channels, they can generally be classified into 4 families of chloride channels that have been identified, with the notable exceptions of ligand gated GABA and glycine receptors: ClC channel proteins, CFTR (cystic fibrosis transmembrane conductance regulator) channels, calcium-activated chloride channels, and voltage-dependent anion selective channels. [9] Groups are assigned by molecular properties and variance in activation stimuli. CLC channel proteins, which are expressed on cell membranes, organelles, and vesicles, are of particular interest for the development of chloride channel openers due to their regulation of chloride ion transport and gradients for many cellular functions. [7]

ClC Channel Proteins

ClC channel proteins, which were discovered in the 1990s, are found within the plasma and intracellular membranes of cells. [10] Expressed as either anion channels or anion/protein exchangers, these proteins can join to form homomeric or heteromeric dimers. [10] [6] These proteins have both individual pathways as well as advanced pathway options when incorporated into a dimer. The specific channel and exchanger biological function roles vary based on organism type. The ClC-1 channel protein, the first identified member of this protein family, elicited extraordinary scientific interest when it was discovered to possess two gates or channels which functioned independently of one another [11] This so-called “double-barreled” structure poses both a potential for new understanding and very complex drug design utilizing the surprising structure of the ClC-1 protein. [7]

CFTR Channels

The cystic fibrosis transmembrane conductance regulator (CFTR) is a phosphorylation-dependent epithelial chloride channel located mostly within the apical membrane of epithelial cells to control the rate of chloride ion flow. [12] The CFTR channels are therefore critical to determining transepithelial salt transport, fluid flow, and concentrations of ions. CFTR chloride channels have important roles in various aspects of the human body, such as in fluid and electrolyte secretion within the intestines, pancreas, and sweat glands. The structure of the CFTR consists of five domains: two nucleotide-binding domains, two membrane-spanning domains , and a single regulatory domain. [12] Each of the domains has a different contribution to the overall function of the CFTR chloride channel. The membrane-spanning domains create the channel pore, while the phosphorylation of the regulatory domain controls the activity of the channels, and ATP hydrolysis from the nucleotide-binding domains modulates gating of the channels. [12] When CFTR channels malfunction, the transport of chloride ions across epithelial cells is disturbed, impacting the function of various organs lined by these cells, and leading to the genetic disorder cystic fibrosis. [12] As a result, the CFTR channels also represent a key target for the development of chloride channel agonists.

Calcium-activated Chloride Channels

The calcium-activated chloride channel family (CaCCs) are present throughout a wide range of tissues, participating in several physiological processes including epithelial secretion, sensory transduction, and smooth muscle contraction. [13] CaCCs are activated by cytosolic calcium ions, and moderate transmembrane anion transport in response to an increase in the intracellular concentration of calcium ions. [14] The most notable CaCC is formed by TMEM16A, which is present in several tissues of the body. TMEM16A has a variety of different functions within the various tissues it is present in, such as in chloride ion secretion with the airway epithelia, making it an important target for the development of chloride modulating drugs which treat cystic fibrosis. [14]

Voltage-dependent Anion Selective Channels

Voltage-dependent anion selective channels (VDAC), which are also known as mitochondrial porins, are channels permeable to a variety of anions, cations, and other metabolites including ATP. [15] At lower transmembrane potentials, VDAC channels are more selective for anions such as chloride ions, as opposed to cations, but at higher transmembrane potentials, they favor cations over anions. [15] Therefore, these large-pore channels likely play a key role in regulating the transport of metabolites, including chloride ions, in and out of the mitochondria, and could potentially present as a target for chloride channel modulating drugs. However, other types of chloride channels would likely present a more viable option for the development of channel modulator drugs such as chloride channel agonists.

GABA receptors

GABAergic receptors, which receive GABA, the most prevalent inhibitory neurotransmitter found within the mammalian CNS, can be further divided into three subclasses: GABA-A, GABA-B, and GABA-C. [16] Both GABA-A and GABA–C receptors are ionotropic ligand-gated chloride channels, while the GABA-B receptor is a G-protein-linked metabotropic receptor. [17] The ionotropic GABA-A and GABA-C receptors can be activated by GABA to open and allow entry of negatively chloride ions into a cell, playing a significant role in the control of neuronal excitability. As a result, both GABA-A and GABA-C receptors, particularly GABA-A receptors, represent prominent targets for the development of chloride channel agonist drugs.

GABA-A receptor inhibition

GABA-A receptors are GABA-gated anion channels which are involved in the function of rapid inhibitory synaptic transmission through the vertebrate CNS [18] [28]. These receptors are coupled with intrinsic chloride channels that are triggered to open through the binding of GABA, which is an inhibitory neurotransmitter. [11] When activated, GABAergic inhibition of two types, phasic and tonic, will occur. [16] Phasic GABA-A receptor-mediated inhibition is a result of a brief exposure of postsynaptic GABA-A receptors to high concentrations of GABA. Alternatively, tonic GABA-A receptor-mediated inhibition results from an activation of extrasynaptic receptors by low concentrations of ambient GABA. [16] Somewhere between 75% and 90% of GABA-A inhibition in the CNS is tonic. [16]

GABA-A receptor structure and disease

GABA-A receptors are part of the cys-loop pentameric ligand-gated ion channel family, which includes multiple neurotransmitter-gated channels. [11] GABAA receptors are assembled from five subunits. Such subunits and splice variants can be distinguished as α1-α6, β1-β3, γ1-γ3, δ, ε, π and θ. [16] GABA-A receptor subunit mutations are believed to be a potential cause for many neurological and CNS disorders. For example, epilepsy related sleep disturbances are believed to be partially caused by improper activation of the β3 GABA-A receptor subunit. [16] Various other pathological mood disorders including anxiety and schizophrenia are major therapeutic targets for GABA-A. [16] GABA-A therapeutics are a related therapy that could potentially be treated or targeted by chloride ion channel opener drugs.

Perception of chloride ion gated channels as drug targets

Chloride channels were largely overlooked as drug targets for many years with a greater emphasis placed on ligand gated channels due to the high selectivity (easy targeting) of ligands in comparison to chloride ions. [7] [11] Outside of the discovery of the GABA-A receptors, chloride channels have remained understudied in the world of drug therapeutics. [6] [7] [11] The discovery of GABA-A receptors has allowed the scientific community to see that chloride channels could have a direct link to central nervous system (CNS) cell operation. [7] However, the lack of a complete understanding of the precise workings of chloride channels hinders the creation of drugs which can modulate these channels with a high level of specificity.

Channel Modulators Overview

Channel Modulators

Channel modulating drugs, otherwise known as ion channel modulators, belong to a category of drugs which control the operation of ion channels. Channel modulators can act as either blockers or openers of these channels, and can either directly or indirectly modulate ion channels. Ion channel modulation is of great significance in drug development, as ion channel modulators can be used to treat a wide variety of medical conditions, including diabetes and hypertension. [19]

Targeting Ion Channels

Ion channels are significant drug targets due to their importance in a vast range of physiological processes. [20] However, the development of ion channel modulating drugs has historically been challenging due to certain factors such target specificity, structural complexity of ion channel proteins, identification of drug binding sites, and the drug screening methods. Regarding specificity, as ion channels have a variety of different functions, a lack of selectivity can cause undesirable side effects from channel modulators. [21]

Mechanism of Action

There are a variety of factors that contribute to the activation of chloride channels. Some of the factors contributing to CLC activation would be cellular swelling, chloride imbalance, intracellular Ca2+ signaling, membrane potential changes, and intracellular pH changes, among others. [22]

One example of a common chloride channel activator which is used to treat both constipation caused by IBS (irritable bowel syndrome) as well as cystic fibrosis would be Lubiprostone. [23] This drug is poorly absorbed following oral administration, until its eventual metabolization within the stomach and the small intestine (specifically the jejunum). After it is metabolized, Lubiprostone utilizes membrane stimulation to selectively stimulate CLC-2 (type 2 chloride channels) channels leading to a pathway that releases fluids, relieving symptoms. Another example would be the drug ivermectin which binds to glutamate-gated chloride channel receptors, triggering them to open and allow chloride ions to flow into a cell. [24] [25] Ivermectin binds in the transmembrane domain of the glutamate-gated chloride channel receptors, allowing for an open-pore conformation. [24]

ivermectin (shown in dark blue) bound to the glutamate-gated chloride channel receptor (shown in turquoise). From PDB: 3RHW . Glutamate-gated chloride channel receptor with bound ivermectin 3RHW.png
ivermectin (shown in dark blue) bound to the glutamate-gated chloride channel receptor (shown in turquoise). From PDB: 3RHW ​.

Medical Use/Treatment

The development of drug targets for anion gated channels such as chloride channels has lagged behind the development of cation gated channels due to technical challenges pertaining to the screening methods for chloride-channel modulators. [19] As the technology used for the development of cation and anion gated channel targets is largely similar, many of the strategies used to do so can be applied interchangeably. The major hurdle to the development of chloride gated channel drugs is therefore the screening method. There are an abundance of known toxins that are capable of modulating cations, allowing for molecular characterization of cation gated channels. [19] While it is widely accepted that anion channels are present in every mammalian cell, it has been more difficult to characterize them. [27]

Applications

Treating genetic mutations which cause Cystic Fibrosis

Chloride gated channel opener mutations have been a major pharmacologic target, as dysfunction of this receptor results in common muscular diseases such as hyperekplexia and even depressive disorders. [3] One such musculoskeletal disorder that is also influenced by mutations in chloride gated channels is cystic fibrosis [28] [5]. A mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is the most common mutation causing cystic fibrosis and has, therefore, been a logical target for therapeutics. [28] The specific mutation is a deletion of the amino acid residue phenylalanine at position 508 (DeltaF508). A class of natural coumarin compounds, identified by scientists, is capable of correcting the defective chloride channel gating. [28] The compound, which is a Chinese medicinal herb, was mixed with a cAMP (cyclic adenosine monophosphate) agonist and exposed to a mutation in question. [28] The DeltaF508-CFTR was activated by the coumarin and cAMP agonist mixture. Upon washing the coumarin from the assay, the activation of the DeltaF508-CFTR was terminated. [28] This innovation indicates that natural lead compounds could be used as chloride channel opener drugs.

Treating CNS/Neurological Disorders

Many of the functions of the Central Nervous System (CNS) rely heavily upon the homeostasis of chloride ion levels. While chloride channels (CLC) and ion transporters are both useful in regulating this homeostasis, chloride channels provide a quicker response to changes in molecular levels, making them essential to CNS function. [7] In particular, CLC-1 and CLC-2 channels play essential roles in the function of the CNS; their dysfunction or mutation can lead to neurological disorders. CLC-1 is present in the hippocampus, frontal neocortex, and nuclei of the brainstem and thalamus. Due to its role in physiological processes such as neuronal network maturation and excitability, manipulation of the chloride channel has been linked to diseases such as epilepsy. [29] Multiple companies have created chloride channel targeting drugs with the intent of modulating/altering CLC-1 function, such as Acetazolamide (a drug that elevates chloride conductance, acting as a chloride channel opener) and NMD670, a CLC-1 inhibitor. [7] [30] CLC-2 is more commonly expressed in the CNS and thus contributes to a wide array of functions that can lead to disease states if mutated. In particular, CLC-2 mediates chloride currents and aids with blood flow and neuroprotection of the hippocampus. CLC-2 channel dimers have protopores that can be opened individually or together via a common gating process activated by hyperpolarization. [31] Drugs such as Omeprazole and Lubistiprone seek to activate CLC-2 channels in specific areas utilizing their ability to be activated by methods such as extracellular pH shift. CLC-2 has also been linked to neurological diseases such as epilepsy.

Treating Epilepsy

As one of the most common neurological disorders, epilepsy is an advantageous target for treatment. [16] It is believed that epilepsy is associated with extremely high levels of calcium, up to 2-5 times the normal physiological levels of calcium. [16] Propositions have been made to utilize the relationship between extracellular and intracellular ions to regulate high and persistently high levels of calcium when applicable. Though this approach could, in theory, be a solution, the lack of success in studies targeting calcium channels for this expressed purpose have been mostly abandoned [16] [27]. Thus, the likelihood of further investment in chloride ion channel openers as opposed to calcium ion channel openers is low without significant scientific discovery or innovation.

Future Perspectives

Future research on chloride channel opener drugs will likely involve the complete translation of chloride channel opener research from concept to incorporation into human medicine. While chloride channel openers, and modulators in general, are gaining traction as a promising treatment target for diseases such as cystic fibrosis, there are very few treatments that have progressed past animal models. [32] Indeed, Lubistiprone (trade name: Amitiza) is one of the only commercially available uses of chloride channel openers in humans. [33]

One of the major issues preventing the development of not only chloride channel openers, but any channel modulators specifically targeting chloride channels would be the relatively poor understanding of certain aspects of chloride channels themselves. Although a vast range of information is available regarding chloride channel function and physiological roles, there are gaps in the present literature, such as the molecular identification of volume-sensitive chloride channels. [3] The relatively intricate and complex structures of chloride channel proteins and the somewhat limited knowledge of certain types of chloride channels creates obstacles for the development of chloride channel modulators. Most notably, this lack of understanding results in difficulties in developing chloride channel modulators with a high level of specificity. Further research regarding the functioning and properties of chloride channels would be necessary in order to overcome this barrier to the development of drugs targeting them.

Regarding the future direction of chloride channel opener drug development, research will likely proceed to the exploration of applications outside of the realm of cystic fibrosis. It has been observed that mutations in chloride channel proteins can result in a multitude of diseases and disorders beyond cystic fibrosis due to their importance in several biological processes. For example, mutated chloride channels can cause osteoporosis, kidney stones, muscle disorder myotonia, and more. [34] Due to the diverse set of conditions that are linked to chloride channel proteins, there is great potential for future research into chloride channel openers for conditions outside of cystic fibrosis such as epilepsy and other neurological diseases affected by CLCs.

See also

Related Research Articles

<span class="mw-page-title-main">Ion channel</span> Pore-forming membrane protein

Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.

<span class="mw-page-title-main">Cystic fibrosis</span> Genetic disorder affecting mostly the lungs

Cystic fibrosis (CF) is a genetic disorder inherited in an autosomal recessive manner that impairs the normal clearance of mucus from the lungs, which facilitates the colonization and infection of the lungs by bacteria, notably Staphylococcus aureus. CF is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. The hallmark feature of CF is the accumulation of thick mucus in different organs. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. Other signs and symptoms may include sinus infections, poor growth, fatty stool, clubbing of the fingers and toes, and infertility in most males. Different people may have different degrees of symptoms.

<span class="mw-page-title-main">Neurotransmitter receptor</span> Type of protein

A neurotransmitter receptor is a membrane receptor protein that is activated by a neurotransmitter. Chemicals on the outside of the cell, such as a neurotransmitter, can bump into the cell's membrane, in which there are receptors. If a neurotransmitter bumps into its corresponding receptor, they will bind and can trigger other events to occur inside the cell. Therefore, a membrane receptor is part of the molecular machinery that allows cells to communicate with one another. A neurotransmitter receptor is a class of receptors that specifically binds with neurotransmitters as opposed to other molecules.

An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential. The opposite of an inhibitory postsynaptic potential is an excitatory postsynaptic potential (EPSP), which is a synaptic potential that makes a postsynaptic neuron more likely to generate an action potential. IPSPs can take place at all chemical synapses, which use the secretion of neurotransmitters to create cell-to-cell signalling. EPSPs and IPSPs compete with each other at numerous synapses of a neuron. This determines whether an action potential occurring at the presynaptic terminal produces an action potential at the postsynaptic membrane. Some common neurotransmitters involved in IPSPs are GABA and glycine.

<span class="mw-page-title-main">Antiporter</span> Class of transmembrane transporter protein

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<span class="mw-page-title-main">Cystic fibrosis transmembrane conductance regulator</span> Mammalian protein found in humans

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<span class="mw-page-title-main">Chloride channel</span> Class of transport proteins

Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration in vivo is much higher than other anions. Several families of voltage-gated channels and ligand-gated channels have been characterized in humans.

GABA<sub>A</sub> receptor Ionotropic receptor and ligand-gated ion channel

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H+/Cl− exchange transporter 3 is a protein that in humans is encoded by the CLCN3 gene.

<span class="mw-page-title-main">Channel blocker</span> Molecule able to block protein channels, frequently used as pharmaceutical

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<span class="mw-page-title-main">Gating (electrophysiology)</span>

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Paul Adrian Negulescu is an American–Romanian cell biologist. He is a Senior Vice President at American pharmaceutical company Vertex Pharmaceuticals. He received the 2022 Shaw Prize in Life science and medicine, together with Michael J. Welsh, for their work that uncovered the etiology of cystic fibrosis and developed effective medications.

Michael James Welsh is an American pulmonologist. He is the current Roy J. Carver Chair in Biomedical Research, the Professor of Internal Medicine in Pulmonary, Critical Care and Occupational Medicine at the Department of Internal Medicine, and the Director of Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa. He is also a professor at the Department of Neurosurgery, Department of Neurology, and Department of Molecular Physiology and Biophysics. He received the 2022 Shaw Prize in Life science and Medicine, together with Paul A. Negulescu, for their work that uncovered the etiology of cystic fibrosis and developed effective medications.

References

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  17. ↑ Yongchang, Chang (2005). "Structural Bases of Ionotropic GABA Receptor Function and Modulation*". Barrow Quarterly. 21 (3).
  18. ↑ Goetz, T., Arslan, A., Wisden, W., & Wulff, P. (2007). "GABAA receptors: Structure and function in the basal ganglia". GABA(A) receptors: structure and function in the basal ganglia. Progress in Brain Research. Vol. 160. pp. 21–41. doi:10.1016/S0079-6123(06)60003-4. ISBN   978-0-444-52184-2. PMC   2648504 . PMID   17499107.{{cite book}}: CS1 maint: multiple names: authors list (link)
  19. 1 2 3 Birch, P. (May 2004). "Strategies to identify ion channel modulators: Current and novel approaches to target neuropathic pain". Drug Discovery Today. 9 (9): 410–418. doi:10.1016/s1359-6446(04)03043-0. PMID   15081958.
  20. ↑ Gregory J. Kaczorowski, Owen B. McManus, Birgit T. Priest, Maria L. Garcia (April 2008). "Ion Channels as Drug Targets: The Next GPCRs". Journal of General Physiology. 131 (5): 399–405. doi:10.1085/jgp.200709946. PMC   2346569 . PMID   18411331.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ↑ Liszewski, Kathy (15 June 2007). "Opening the Gates on Ion Channel Drugs". Genetic Engineering & Biotechnology News.
  22. ↑ Rahmati, N., Hoebeek, F. E., Peter, S., & De Zeeuw, C. I. (May 2018). "Chloride homeostasis in neurons with special emphasis on the olivocerebellar system: Differential roles for transporters and channels". Frontiers in Cellular Neuroscience. 12: 101. doi: 10.3389/fncel.2018.00101 . PMC   5938380 . PMID   29765304.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ↑ Lunsford, T. N., & Harris, L. A. (October 2010). "Lubiprostone: evaluation of the newest medication for the treatment of adult women with constipation-predominant irritable bowel syndrome". International Journal of Women's Health. 2: 361–374. doi: 10.2147/IJWH.S4537 . PMC   2990905 . PMID   21151683.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. 1 2 Hibbs, R. E., & Gouaux, E. (May 2011). "Principles of activation and permeation in an anion-selective Cys-loop receptor". Nature. 474 (7349): 54–60. doi:10.1038/nature10139. PMC   3160419 . PMID   21572436.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ↑ Atif, M., Estrada-Mondragon, A., Nguyen, B., Lynch, J. W., & Keramidas, A. (October 2017). "ffects of glutamate and ivermectin on single glutamate-gated chloride channels of the parasitic nematode H. contortus". PLOS Pathogens. 13 (10): e1006663. doi: 10.1371/journal.ppat.1006663 . PMC   5638611 . PMID   28968469.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  26. ↑ Atif M, Estrada-Mondragon A, Nguyen B, Lynch JW, Keramidas A (October 2017). "Effects of glutamate and ivermectin on single glutamate-gated chloride channels of the parasitic nematode H. contortus". PLOS Pathog. 13 (10): e1006663. doi: 10.1371/journal.ppat.1006663 . PMC   5638611 . PMID   28968469.
  27. ↑ Lambert, S., & Oberwinkler, J. (2005). "Characterization of a proton-activated, outwardly rectifying anion channel". The Journal of Physiology. 567 (Pt 1): 191–213. doi:10.1113/jphysiol.2005.089888. PMC   1474181 . PMID   15961423.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. 1 2 3 4 5 Xu, L., Na, W., Liu, X., Hou, S., Lin, S., Yang, H., & Ma, T. (July 2008). "Identification of natural coumarin compounds that rescue defective ΔF508-CFTR Chloride Channel gating". Clinical and Experimental Pharmacology and Physiology. 35 (8): 878–883. doi:10.1111/j.1440-1681.2008.04943.x. PMID   18430055.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ↑ Chen, T. T., Klassen, T. L., Goldman, A. M., Marini, C., Guerrini, R., & Noebels, J. L. (March 2013). "Novel brain expression of ClC-1 chloride channels and enrichment of CLCN1 variants in epilepsy". Neurology. 80 (12): 1078–1085. doi:10.1212/WNL.0b013e31828868e7. PMC   3662306 . PMID   23408874.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  30. ↑ Eguchi, H., Tsujino, A., Kaibara, M., Hayashi, H., Shirabe, S., Taniyama, K., & Eguchi, K. (June 2006). "Acetazolamide acts directly on the human skeletal muscle chloride channel". Muscle & Nerve. 34 (3): 292–297. doi:10.1002/mus.20585. PMID   16770776.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  31. ↑ Bi, M. M., Hong, S., Zhou, H. Y., Wang, H. W., Wang, L. N., & Zheng, Y. J. (2013). "Chloride channelopathies of ClC-2". International Journal of Molecular Sciences. 15 (1): 218–249. doi: 10.3390/ijms15010218 . PMC   3907807 . PMID   24378849.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  32. ↑ Verkman, A. S., & Galietta, L. J. (November 2021). "Chloride transport modulators as drug candidates". American Journal of Physiology. Cell Physiology. 321 (6): C932–C946. doi:10.1152/ajpcell.00334.2021. PMC   8714991 . PMID   34644122.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  33. ↑ Shaffer, Chad. "Chloride channel activators: Uses, common brands, and safety info". SingleCare.
  34. ↑ Jentsch, T. J., Maritzen, T., & Zdebik, A. A. (August 2005). "Chloride channel diseases resulting from impaired transepithelial transport or vesicular function". The Journal of Clinical Investigation. 115 (8): 2039–2046. doi:10.1172/JCI25470. PMC   1180548 . PMID   16075045.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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