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Journal articles on the topic 'Chloride channels'
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1
Lísal, Jiří, and Merritt Maduke. "Proton-coupled gating in chloride channels." Philosophical Transactions of the Royal Society B: Biological Sciences 364, no. 1514 (October 28, 2008): 181–87. http://dx.doi.org/10.1098/rstb.2008.0123.
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The physiologically indispensable chloride channel (CLC) family is split into two classes of membrane proteins: chloride channels and chloride/proton antiporters. In this article we focus on the relationship between these two groups and specifically review the role of protons in chloride-channel gating. Moreover, we discuss the evidence for proton transport through the chloride channels and explore the possible pathways that the protons could take through the chloride channels. We present results of a mutagenesis study, suggesting the feasibility of one of the pathways, which is closely related to the proton pathway proposed previously for the chloride/proton antiporters. We conclude that the two groups of CLC proteins, although in principle very different, employ similar mechanisms and pathways for ion transport.
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Jentsch, Thomas J. "Chloride channels." Current Opinion in Neurobiology 3, no. 3 (June 1993): 316–21. http://dx.doi.org/10.1016/0959-4388(93)90123-g.
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Kicińska, A., G. D bska, W. Kunz, and A. Szewczyk. "Mitochondrial potassium and chloride channels." Acta Biochimica Polonica 47, no. 3 (September 30, 2000): 541–51. http://dx.doi.org/10.18388/abp.2000_3977.
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Channels selective for potassium or chloride ions are present in inner mitochondrial membranes. They probably play an important role in mitochondrial events such as the formation of delta pH and regulation of mitochondrial volume changes. Mitochondrial potassium and chloride channels could also be the targets for pharmacologically active compounds such as potassium channel openers and antidiabetic sulfonylureas. This review describes the properties, pharmacology, and current observations concerning the functional role of mitochondrial potassium and chloride channels.
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Kim, Hyeong Jae, Peter Chang-Whan Lee, and Jeong Hee Hong. "Chloride Channels and Transporters: Roles beyond Classical Cellular Homeostatic pH or Ion Balance in Cancers." Cancers 14, no. 4 (February 9, 2022): 856. http://dx.doi.org/10.3390/cancers14040856.
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The canonical roles of chloride channels and chloride-associated transporters have been physiologically determined; these roles include the maintenance of membrane potential, pH balance, and volume regulation and subsequent cellular functions such as autophagy and cellular proliferative processes. However, chloride channels/transporters also play other roles, beyond these classical function, in cancerous tissues and under specific conditions. Here, we focused on the chloride channel-associated cancers and present recent advances in understanding the environments of various types of cancer caused by the participation of many chloride channel or transporters families and discuss the challenges and potential targets for cancer treatment. The modulation of chloride channels/transporters might promote new aspect of cancer treatment strategies.
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Duszyk, Marek, Andrew S. French, and S. F. Paul Man. "Cystic fibrosis affects chloride and sodium channels in human airway epithelia." Canadian Journal of Physiology and Pharmacology 67, no. 10 (October 1, 1989): 1362–65. http://dx.doi.org/10.1139/y89-217.
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Abnormalities of epithelial function in cystic fibrosis (CF) have been linked to defects in cell membrane permeability to chloride or sodium ions. Recently, a class of chloride channels in airway epithelial cells have been reported to lack their usual sensitivity to phosphorylation via cAMP-dependent protein kinase, suggesting that CF could be due to a single genetic defect in these channels. We have examined single chloride and sodium channels in control and CF human nasal epithelia using the patch-clamp technique. The most common chloride channel was not the one previously associated with CF, but it was also abnormal in CF cells. In addition, the number of sodium channels was unusually high in CF. These findings suggest a wider disturbance of ion channel properties in CF than would be produced by a defect in a single type of channel.Key words: ion channels, cystic fibrosis, airway, epithelium.
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Uchida, Shinichi. "In vivo role of CLC chloride channels in the kidney." American Journal of Physiology-Renal Physiology 279, no. 5 (November 1, 2000): F802—F808. http://dx.doi.org/10.1152/ajprenal.2000.279.5.f802.
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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.
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Wilczyński, Bartosz, Alicja Dąbrowska, Jolanta Saczko, and Julita Kulbacka. "The Role of Chloride Channels in the Multidrug Resistance." Membranes 12, no. 1 (December 28, 2021): 38. http://dx.doi.org/10.3390/membranes12010038.
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Nowadays, one of medicine’s main and most challenging aims is finding effective ways to treat cancer. Unfortunately, although there are numerous anti-cancerous drugs, such as cisplatin, more and more cancerous cells create drug resistance. Thus, it is equally important to find new medicines and research the drug resistance phenomenon and possibilities to avoid this mechanism. Ion channels, including chloride channels, play an important role in the drug resistance phenomenon. Our article focuses on the chloride channels, especially the volume-regulated channels (VRAC) and CLC chloride channels family. VRAC induces multidrug resistance (MDR) by causing apoptosis connected with apoptotic volume decrease (AVD) and VRAC are responsible for the transport of anti-cancerous drugs such as cisplatin. VRACs are a group of heterogenic complexes made from leucine-rich repetition with 8A (LRRC8A) and a subunit LRRC8B-E responsible for the properties. There are probably other subunits, which can create those channels, for example, TTYH1 and TTYH2. It is also known that the ClC family is involved in creating MDR in mainly two mechanisms—by changing the cell metabolism or acidification of the cell. The most researched chloride channel from this family is the CLC-3 channel. However, other channels are playing an important role in inducing MDR as well. In this paper, we review the role of chloride channels in MDR and establish the role of the channels in the MDR phenomenon.
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Zhao, Piao, Cheng Tang, Yuqin Yang, Zhen Xiao, Samantha Perez-Miller, Heng Zhang, Guoqing Luo, et al. "A new polymodal gating model of the proton-activated chloride channel." PLOS Biology 21, no. 9 (September 15, 2023): e3002309. http://dx.doi.org/10.1371/journal.pbio.3002309.
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The proton–activated chloride (PAC) channel plays critical roles in ischemic neuron death, but its activation mechanisms remain elusive. Here, we investigated the gating of PAC channels using its novel bifunctional modulator C77304. C77304 acted as a weak activator of the PAC channel, causing moderate activation by acting on its proton gating. However, at higher concentrations, C77304 acted as a weak inhibitor, suppressing channel activity. This dual function was achieved by interacting with 2 modulatory sites of the channel, each with different affinities and dependencies on the channel’s state. Moreover, we discovered a protonation–independent voltage activation of the PAC channel that appears to operate through an ion–flux gating mechanism. Through scanning–mutagenesis and molecular dynamics simulation, we confirmed that E181, E257, and E261 in the human PAC channel serve as primary proton sensors, as their alanine mutations eliminated the channel’s proton gating while sparing the voltage–dependent gating. This proton–sensing mechanism was conserved among orthologous PAC channels from different species. Collectively, our data unveils the polymodal gating and proton–sensing mechanisms in the PAC channel that may inspire potential drug development.
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Fahlke, Christoph, Timothy Knittle, Christina A. Gurnett, Kevin P. Campbell, and Alfred L. George. "Subunit Stoichiometry of Human Muscle Chloride Channels." Journal of General Physiology 109, no. 1 (January 1, 1997): 93–104. http://dx.doi.org/10.1085/jgp.109.1.93.
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Voltage-gated Cl− channels belonging to the ClC family appear to function as homomultimers, but the number of subunits needed to form a functional channel is controversial. To determine subunit stoichiometry, we constructed dimeric human skeletal muscle Cl− channels in which one subunit was tagged by a mutation (D136G) that causes profound changes in voltage-dependent gating. Sucrose-density gradient centrifugation experiments indicate that both monomeric and dimeric hClC-1 channels in their native configurations exhibit similar sedimentation properties consistent with a multimeric complex having a molecular mass of a dimer. Expression of the heterodimeric channel in a mammalian cell line results in a homogenous population of Cl− channels exhibiting novel gating properties that are best explained by the formation of heteromultimeric channels with an even number of subunits. Heteromultimeric channels were not evident in cells cotransfected with homodimeric WT-WT and D136G-D136G constructs excluding the possibility that functional hClC-1 channels are assembled from more than two subunits. These results demonstrate that the functional hClC-1 unit consists of two subunits.
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Higgins, Chris. "Chloride channels revisited." Nature 358, no. 6387 (August 1992): 536. http://dx.doi.org/10.1038/358536a0.
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Vinson, V. "Controlling Chloride Channels." Science Signaling 3, no. 146 (November 2, 2010): ec338-ec338. http://dx.doi.org/10.1126/scisignal.3146ec338.
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Bretag, A. H. "Muscle chloride channels." Physiological Reviews 67, no. 2 (April 1987): 618–724. http://dx.doi.org/10.1152/physrev.1987.67.2.618.
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Ackerman, Michael J., and David E. Clapham. "Cardiac chloride channels." Trends in Cardiovascular Medicine 3, no. 1 (January 1993): 23–28. http://dx.doi.org/10.1016/1050-1738(93)90024-z.
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Gabriel, S. E., E. M. Price, R. C. Boucher, and M. J. Stutts. "Small linear chloride channels are endogenous to nonepithelial cells." American Journal of Physiology-Cell Physiology 263, no. 3 (September 1, 1992): C708—C713. http://dx.doi.org/10.1152/ajpcell.1992.263.3.c708.
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We used both single-channel and whole cell patch-clamp techniques to characterize chloride channels and currents endogenous to Sf9 cells, 3T3 fibroblasts, and Chinese hamster ovary cells. In cell-attached patches from these cell types, anion channels were observed with low ohmic conductance (4-11 ps), linear current-voltage relationships, and little time- or voltage-dependent behavior. These channels are very similar to the Cl- channels reported to appear concomitant with the expression of cystic fibrosis transmembrane conductance regulator (CFTR) in these cell lines. The presence of such endogenous channels suggests either that low levels of CFTR are present in all of these cell lines prior to transfection or that an endogenous non-CFTR channel is present in these cell types. Our results suggest that at least some of the channel behaviors attributed to expressed, recombinant CFTR in previous studies may have been due to these endogenous Cl- channels.
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Debska, G., A. Kicińska, J. Skalska, and A. Szewczyk. "Intracellular potassium and chloride channels: an update." Acta Biochimica Polonica 48, no. 1 (March 31, 2001): 137–44. http://dx.doi.org/10.18388/abp.2001_5120.
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Channels selective for potassium or chloride ions are present in all intracellular membranes such as mitochondrial membranes, sarcoplasmic/endoplasmic reticulum, nuclear membrane and chromaffin granule membranes. They probably play an important role in events such as acidification of intracellular compartments and regulation of organelle volume. Additionally, intracellular ion channels are targets for pharmacologically active compounds, e.g. mitochondrial potassium channels interact with potassium channel openers such as diazoxide. This review describes current observations concerning the properties and functional roles of intracellular potassium and chloride channels.
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Fahlke, Christoph. "Ion permeation and selectivity in ClC-type chloride channels." American Journal of Physiology-Renal Physiology 280, no. 5 (May 1, 2001): F748—F757. http://dx.doi.org/10.1152/ajprenal.2001.280.5.f748.
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Voltage-gated anion channels are present in almost every living cell and have many physiological functions. Recently, a novel gene family encoding voltage-gated chloride channels, the ClC family, was identified. The knowledge of primary amino acid sequences has allowed for the study of these anion channels in heterologous expression systems and made possible the combination of site-directed mutagenesis and high-resolution electrophysiological measurements as a means of gaining insights into the molecular basis of channel function. This review focuses on one particular aspect of chloride channel function, the selective transport of anions through biological membranes. I will describe recent experiments using a combination of cellular electrophysiology, molecular genetics, and recombinant DNA technology to study the molecular basis of ion permeation and selection in ClC-type chloride channels. These novel tools have provided new insights into basic mechanisms underlying the function of these biologically important channels.
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Darvish, N., J. Winaver, and D. Dagan. "Diverse modulations of chloride channels in renal proximal tubules." American Journal of Physiology-Renal Physiology 267, no. 5 (November 1, 1994): F716—F724. http://dx.doi.org/10.1152/ajprenal.1994.267.5.f716.
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Cl- selective channels were detected and characterized in apical membranes of cultured rat renal proximal convoluted tubule cells (PCT) using patch-clamping methods. Subpopulations of Cl- channels modulated by cyclic nucleotides, Ca2+, or voltage were identified. Two different 30-pS, voltage-independent, Cl- channels modulated by adenosine 3',5'-cyclic monophosphate (cAMP) or Ca2+ were seen most frequently. The cAMP-dependent channel was activated by membrane-permeable analogues of cAMP, dibutyryl-cAMP or 8-bromo-cAMP. Catalytic subunit of protein kinase A (PKA) applied to detached inside-out patches, activated the channel as well, suggesting activation via phosphorylation. Channel activity was blocked by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, by 4,4-dinitrostilbene-2,2-disulfonic acid, and by SCN-. Permeability sequence for different halides was Cl- > I > F with a Cl(-)-to-cation permeability ratio (PCl/Pcation) of 7:1. The Ca(2+)-sensitive channel was not activated by cAMP nor by PKA. A third anionic selective channel encountered infrequently is voltage dependent and has a unitary conductance of 145 pS, with a PCl/Pcation value of 9:1. This diversity of Cl- channels may underlie the rich repertoire of physiological functions attributed to Cl- channels.
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al-Awqati, Q., J. Barasch, and D. Landry. "Chloride channels of intracellular organelles and their potential role in cystic fibrosis." Journal of Experimental Biology 172, no. 1 (November 1, 1992): 245–66. http://dx.doi.org/10.1242/jeb.172.1.245.
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Chloride channels were previously purified from bovine kidney cortex membranes using a drug affinity column. Reconstitution of the purified proteins into artificial liposomes and planar bilayers yielded chloride channels. A 64 x 10(3) M(r) protein, p64, identified as a component of this chloride channel, was used to generate antibodies which depleted solubilized kidney membranes of all chloride channel activity. This antibody has now been used to identify a clone, H2B, from a kidney cDNA library. Antibodies, affinity-purified against the fusion protein of H2B, from a kidney cDNA library. Antibodies, affinity-purified against the fusion protein of H2B, also depleted solubilized kidney cortex from all chloride channel activity. The predicted amino acid sequence of p64 shows that it contains two and possibly four putative transmembrane domains and potential phosphorylation sites by protein kinases A and C. There was no significant homology to other protein (or DNA) sequences in the data base including other anion channels or the cystic fibrosis transmembrane conductance regulator. The protein is expressed in all cells tested and probably represents the chloride channel of intracellular organelles. Cystic fibrosis (CF) is associated with a defect in a cyclic-AMP-activated chloride channel in secretory epithelia which leads to decreased fluid secretion. In addition, many mucus glycoproteins show decreased sialylation but increased sulfation. We have recently shown that the pH of intracellular organelles is more alkaline in CF cells, an abnormality that is due to defective chloride conductance in the vesicle membranes. We postulate that the defect in the intracellular chloride channel, and hence the alkalization, could explain the glycosylation abnormalities since the pH optimum of Golgi sialyltransferase is acid while that of focusyl- and sulfotransferases is alkaline. Defects in sialyation of glycolipids might also generate receptors for Pseudomonas, which is known to colonize the respiratory tract of CF patients.
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Thompson, Gregory W., Magda Horackova, and J. Andrew Armour. "Ion channel modifying agents influence the electrical activity generated by canine intrinsic cardiac neurons in situ." Canadian Journal of Physiology and Pharmacology 78, no. 4 (March 1, 2000): 293–300. http://dx.doi.org/10.1139/y99-138.
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This study was designed to establish whether agents known to modify neuronal ion channels influence the behavior of mammalian intrinsic cardiac neurons in situ and, if so, in a manner consistent with that found previously in vitro. The activity generated by right atrial neurons was recorded extracellularly in varying numbers of anesthetized dogs before and during continuous local arterial infusion of several neuronal ion channel modifying agents. Veratridine (7.5 µM), the specific modifier of Na+-selective channels, increased neuronal activity (95% above control) in 80% of dogs tested (n = 25). The membrane depolarizing agent potassium chloride (40 mM) reduced neuronal activity (43% below control) in 84% of dogs tested (n = 19). The inhibitor of voltage-sensitive K+ channels, tetraethylammonium (10 mM), decreased neuronal activity (42% below control) in 73% of dogs tested (n = 11). The nonspecific potassium channel inhibitor barium chloride (5 mM) excited neurons (47% above control) in 13 of 19 animals tested. Cadmium chloride (200 µM), which inhibits Ca2+-selective channels and Ca2+-dependent K+ channels, increased neuronal activity (65% above control) in 79% of dogs tested (n = 14). The specific L-type Ca2+ channel blocking agent nifedipine (5 µM) reduced neuronal activity (52% blow control in 72% of 11 dogs tested), as did the nonspecific inhibitor of L-type Ca2+ channels, nickel chloride (5 mM) (36% below control in 69% of 13 dogs tested). Each agent induced either excitatory or inhibitory responses, depending on the agent tested. It is concluded that specific ion channels (INa, ICaL, IKv, and IKCa) that have been associated with intrinsic cardiac neurons in vitro are involved in their capacity to generate action potentials in situ.Key words: calcium channels, intrinsic cardiac neuron, potassium channels, sodium channels.
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Hussy, N. "Calcium-activated chloride channels in cultured embryonic Xenopus spinal neurons." Journal of Neurophysiology 68, no. 6 (December 1, 1992): 2042–50. http://dx.doi.org/10.1152/jn.1992.68.6.2042.
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1. Single-channel currents were recorded from Xenopus spinal neurons developing in vitro using the patch-clamp technique, to identify the channels underlying the large and small macroscopic Ca(2+)-activated Cl- currents (ICl(Ca)) present in these cells. 2. Channels of large (maxi-channels; 310 pS) and smaller conductance (mini-channels; 50-60 pS) are activated by elevation of cytoplasmic Ca2+ concentration. Channel activity is not altered by subsequent removal of Ca2+ from the bath, arguing against a direct ligand-type Ca2+ dependence. The much higher incidence of channel activation in cell-attached patches from cells permeabilized with the Ca2+ ionophore A23187 than in excised patches also suggests the involvement of some unidentified intracellular factor. 3. The reversal potential of maxi-Cl- channels is not altered by changes in Na+ concentration, but is shifted in the negative direction by the substitution of Cl- by methanesulfonate on the intracellular side of the patch, indicating their anionic selectivity. 4. Maxi-Cl- channels exhibited the presence of multiple probable subconductance states and showed marked voltage-dependent inactivation above and below +/- 20 mV. 5. Examination of maxi-Cl- channels at early times in culture (6-9 h) and 24 h later did not reveal any developmental change in the characteristics described above. However, the mean open duration of the channel was found to increase twofold during this period of time. 6. The simultaneous presence of maxi- and mini-Cl- channels prevented detailed characterization of the latter. The anionic selectivity of mini-Cl- channels is suggested by their reversal potential that lies close to the Cl- equilibrium potential.(ABSTRACT TRUNCATED AT 250 WORDS)
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Schwiebert, E. M., T. Flotte, G. R. Cutting, and W. B. Guggino. "Both CFTR and outwardly rectifying chloride channels contribute to cAMP-stimulated whole cell chloride currents." American Journal of Physiology-Cell Physiology 266, no. 5 (May 1, 1994): C1464—C1477. http://dx.doi.org/10.1152/ajpcell.1994.266.5.c1464.
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From whole cell patch-clamp recordings at 35 degrees C utilizing either nystatin perforation or conventional methods with 5 mM MgATP in the pipette solution, it was demonstrated that both cystic fibrosis transmembrane conductance regulator (CFTR) chloride (Cl-) channels and outwardly rectifying Cl- channels (ORCC) contribute to adenosine 3',5'-cyclic monophosphate (cAMP)-activated whole cell Cl- currents in cultured human airway epithelial cells. These results were similar whether recordings were performed on two normal human cell lines or on two cystic fibrosis (CF) cell lines stably complemented with wild-type CF gene. These results were obtained by exploiting dissimilar biophysical properties of CFTR and ORCC currents such as the degree of rectification of the current-voltage relationship, the difference in sensitivity to Cl- channel-blocking drugs such as 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), calixarenes, and diphenylamine carboxylic acid (DPC), and the opposing Cl- relative to I- permeabilities of the two channels. In normal cells or complemented CF cells, 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate stimulated outwardly rectifying whole cell Cl- currents. Addition of DIDS in the presence of cAMP inhibited the outwardly rectifying portion of the cAMP-activated Cl- current. The remaining cAMP-activated, DIDS-insensitive, linear CFTR Cl- current was inhibited completely by DPC. Additional results showed that not only do ORCC and CFTR Cl- channels contribute to cAMP-activated Cl- currents in airway epithelial cells where wild-type CFTR is expressed but that both channels fail to respond to cAMP in delta F508-CFTR-containing CF airway cells. We conclude that CFTR not only functions as a cAMP-regulated Cl- channel in airway epithelial cells but also controls the regulation of ORCC.
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Wang, Wei, Claudia Oliva, Ge Li, Arne Holmgren, Christopher Horst Lillig, and Kevin L. Kirk. "Reversible Silencing of CFTR Chloride Channels by Glutathionylation." Journal of General Physiology 125, no. 2 (January 18, 2005): 127–41. http://dx.doi.org/10.1085/jgp.200409115.
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The cystic fibrosis transmembrane conductance regulator (CFTR) is a phosphorylation- and ATP-dependent chloride channel that modulates salt and water transport across lung and gut epithelia. The relationship between CFTR and oxidized forms of glutathione is of potential interest because reactive glutathione species are produced in inflamed epithelia where they may be modulators or substrates of CFTR. Here we show that CFTR channel activity in excised membrane patches is markedly inhibited by several oxidized forms of glutathione (i.e., GSSG, GSNO, and glutathione treated with diamide, a strong thiol oxidizer). Three lines of evidence indicate that the likely mechanism for this inhibitory effect is glutathionylation of a CFTR cysteine (i.e., formation of a mixed disulfide with glutathione): (a) channels could be protected from inhibition by pretreating the patch with NEM (a thiol alkylating agent) or by lowering the bath pH; (b) inhibited channels could be rescued by reducing agents (e.g., DTT) or by purified glutaredoxins (Grxs; thiol disulfide oxidoreductases) including a mutant Grx that specifically reduces mixed disulfides between glutathione and cysteines within proteins; and (c) reversible glutathionylation of CFTR polypeptides in microsomes could be detected biochemically under the same conditions. At the single channel level, the primary effect of reactive glutathione species was to markedly inhibit the opening rates of individual CFTR channels. CFTR channel inhibition was not obviously dependent on phosphorylation state but was markedly slowed when channels were first “locked open” by a poorly hydrolyzable ATP analogue (AMP-PNP). Consistent with the latter finding, we show that the major site of inhibition is cys-1344, a poorly conserved cysteine that lies proximal to the signature sequence in the second nucleotide binding domain (NBD2) of human CFTR. This region is predicted to participate in ATP-dependent channel opening and to be occluded in the nucleotide-bound state of the channel based on structural comparisons to related ATP binding cassette transporters. Our results demonstrate that human CFTR channels are reversibly inhibited by reactive glutathione species, and support an important role of the region proximal to the NBD2 signature sequence in ATP-dependent channel opening.
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THORESON, WALLACE B., RON NITZAN, and ROBERT F. MILLER. "Chloride efflux inhibits single calcium channel open probability in vertebrate photoreceptors: Chloride imaging and cell-attached patch-clamp recordings." Visual Neuroscience 17, no. 2 (March 2000): 197–206. http://dx.doi.org/10.1017/s0952523800172025.
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The present study uses cell-attached patch-recording techniques to study the single-channel properties of Ca2+ channels in isolated salamander photoreceptors and investigate their sensitivity to reductions in intracellular Cl−. The results show that photoreceptor Ca2+ channels possess properties similar to L-type Ca2+ channels in other preparations, including (1) enhancement of openings by the dihydropyridine agonist, (−)BayK8644; (2) suppression by a dihydropyridine antagonist, nisoldipine; (3) single-channel conductance of 22 pS with 82 mM Ba2+ as the charge carrier; (4) mean open probability of 0.1; (5) open-time distribution fit with a single exponential (τ0 = 1.1 ms) consistent with a single open state; and (6) closed time distribution fit with two exponentials (τc1 = 0.7 ms, τc2 = 25.4 ms) consistent with at least two closed states. Using a Cl−-sensitive dye to measure intracellular [Cl−], it was found that perfusion with gluconate-containing, low Cl− medium depleted intracellular [Cl−]. It was therefore possible to reduce intracellular [Cl−] by perfusion with a low Cl− solution while maintaining the extracellular channel surface in high Cl− pipette solution. Under these conditions, the single-channel conductance was unchanged, but the mean open probability fell to 0.03. This reduction can account for the 66% reduction in whole-cell Ca2+ currents produced by perfusion with low Cl− solutions. Examination of the open and closed time distributions suggests that the reduction in open probability arises from increases in closed-state dwell times. Changes in intracellular [Cl−] may thus modulate photoreceptor Ca2+ channels.
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Kulawiak, Bogusz, and Piotr Bednarczyk. "Reconstitution of brain mitochondria inner membrane into planar lipid bilayer." Acta Neurobiologiae Experimentalis 65, no. 3 (September 30, 2005): 271–76. http://dx.doi.org/10.55782/ane-2005-1562.
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Ion channels are present in the inner mitochondrial membrane. They play an important role in cellular processes. Potassium and chloride channels are involved in regulation of mitochondrial volume, membrane potential and acidification. The mitochondrial potassium channels have been suggested as triggers and end effectors in cytoprotection. In our study we measured single channel activities after reconstitution of submitochondrial particles from rat brain mitochondria into planar lipid membranes. After incorporation, two different potassium selective currents were recorded with single channel conductance from 260 to 320 pS and from 70 to 90 pS in gradient (cis/trans) 50/450 and 50/150 mM KCl solutions, respectively. We also observed activity of the chloride ion channel. The measured single channel conductance was from 80 to 90 pS in gradient (cis/trans) 50/450 mM KCl solution. Our results suggest that various ion channels are present in the inner mitochondrial membrane of brain mitochondria.
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Gray, R., and D. Johnston. "Rectification of single GABA-gated chloride channels in adult hippocampal neurons." Journal of Neurophysiology 54, no. 1 (July 1, 1985): 134–42. http://dx.doi.org/10.1152/jn.1985.54.1.134.
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The properties of single chloride channels activated by gamma-aminobutyric acid (GABA) were investigated with hippocampal slices from adult guinea pigs. After the slices were treated with proteolytic enzymes, gigaseal recordings were made from excised patches of pyramidal or granule cell membranes. This newly developed preparation permits the application of patch-clamp techniques to the adult mammalian central nervous system. Guinea pig hippocampal slices were prepared in a conventional manner. Once prepared, the slices were treated with two different enzymes for brief periods and gently agitated. Slices generally split apart along the boundaries of the cell body regions, exposing neuronal somata. Standard patch-clamp techniques were used for the gigaseal recordings from excised patches. Solutions for both sides of the patches consisted of symmetrical concentrations of chloride, with all cation channels blocked. GABA at concentrations of 0.5-1.0 microM was added to the solution for the extracellular side of the patches. At transmembrane potentials negative to the chloride reversal potential (0 mV), the conductance through the GABA-gated chloride channels was approximately 20 pS. When the transmembrane potential was changed to positive values, the chloride conductance increased dramatically. For example, at +40 mV the conductance through the GABA-gated channels was almost 40 pS. Ramp-clamp commands were used to measure the current-voltage (I-V) relationship through single open channels. The open-channel I-V curves displayed outward rectification. The relationship between open-channel conductance and voltage could be fitted reasonably well by a single energy-barrier model for the channel, with the higher energy barrier placed near the cytoplasmic side of the membrane (at a fractional distance through the membrane of 0.73).(ABSTRACT TRUNCATED AT 250 WORDS)
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Lidofsky, Steven D., and Richard M. Roman. "Alanine uptake activates hepatocellular chloride channels." American Journal of Physiology-Gastrointestinal and Liver Physiology 273, no. 4 (October 1, 1997): G849—G853. http://dx.doi.org/10.1152/ajpgi.1997.273.4.g849.
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Cells involved in the retrieval and metabolic conversion of amino acids undergo significant increases in size in response to amino acid uptake. The resultant adaptive responses to cell swelling are thought to include increases in membrane K+ and Cl− permeability through activation of volume-sensitive ion channels. This viewpoint is largely based on experimental models of hypotonic swelling, but few mammalian cells experience hypotonic challenge in vivo. Here we have examined volume regulatory responses in a physiological model of cell-swelling alanine uptake in immortalized hepatocytes. Alanine-induced cell swelling was followed by a decrease in cell volume that was temporally associated with an increase in membrane Cl− currents. These currents were dependent both on alanine concentration and Na+, suggesting that currents were stimulated by Na+-coupled alanine uptake. Cl− currents were outwardly rectifying, exhibited an anion permeability sequence of I− > Br− > Cl−, and were inhibited by the Cl− channel blocker 5-nitro-2-(3-phenylpropylamino)benzoic acid, features similar to those reported for a widely distributed class of volume-sensitive anion channels evoked by experimental hypotonic stress. These findings suggest that volume-sensitive anion channels participate in adaptive responses to amino acid uptake and provide such channels with a new physiological context.
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Thakker, Rajesh V. "Chloride channels cough up." Nature Genetics 17, no. 2 (October 1997): 125–27. http://dx.doi.org/10.1038/ng1097-125.
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Hebert, Steven C. "Crystal-clear chloride channels." Nature 379, no. 6564 (February 1996): 398–99. http://dx.doi.org/10.1038/379398a0.
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Jentsch, Thomas J. "Chloride channels are different." Nature 415, no. 6869 (January 2002): 276–77. http://dx.doi.org/10.1038/415276a.
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Zhang, Ya-ping, Hao Zhang, and Dayue Darrel Duan. "Chloride channels in stroke." Acta Pharmacologica Sinica 34, no. 1 (October 29, 2012): 17–23. http://dx.doi.org/10.1038/aps.2012.140.
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Gögelein, Heinz. "Chloride channels in epithelia." Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes 947, no. 3 (October 1988): 521–47. http://dx.doi.org/10.1016/0304-4157(88)90006-8.
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Reeves, W. Brian, and Thomas E. Androli. "Renal Epithelial Chloride Channels." Annual Review of Physiology 54, no. 1 (October 1992): 29–50. http://dx.doi.org/10.1146/annurev.ph.54.030192.000333.
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Hartzell, Criss, Ilva Putzier, and Jorge Arreola. "CALCIUM-ACTIVATED CHLORIDE CHANNELS." Annual Review of Physiology 67, no. 1 (March 17, 2005): 719–58. http://dx.doi.org/10.1146/annurev.physiol.67.032003.154341.
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Wolstenholme, Adrian J. "Glutamate-gated Chloride Channels." Journal of Biological Chemistry 287, no. 48 (October 4, 2012): 40232–38. http://dx.doi.org/10.1074/jbc.r112.406280.
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Gulbins, E., A. Jekle, K. Ferlinz, H. Grassmé, and F. Lang. "Physiology of apoptosis." American Journal of Physiology-Renal Physiology 279, no. 4 (October 1, 2000): F605—F615. http://dx.doi.org/10.1152/ajprenal.2000.279.4.f605.
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Ion fluxes and volume changes of the whole cell as well as of organelles belong to the hallmarks of apoptosis; however, the molecular mechanism regulating these changes is only poorly characterized. Several ion channels in the plasma membrane, in particular the N-type K+channel, the chloride channel cystic fibrosis conductance regulator, and an outward rectifying chloride channel, as well as the mitochondrial permeability transition pore, have been implicated to be involved in signal transduction cascades regulating apoptosis. Furthermore, Bcl-2-like proteins have been suggested to function, at least in part, as ion channels, because they display some homology to bacterial pore-forming toxins. In contrast to the demonstration of the involvement of these different ion channels in apoptosis, the molecular consequences regulated by these ion channels, and finally triggering apoptosis, are almost completely unknown.
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Clancy, J. P., J. D. McCann, M. Li, and M. J. Welsh. "Calcium-dependent regulation of airway epithelial chloride channels." American Journal of Physiology-Lung Cellular and Molecular Physiology 258, no. 2 (February 1, 1990): L25—L32. http://dx.doi.org/10.1152/ajplung.1990.258.2.l25.
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To determine how cell calcium ([Ca2+]c) regulates apical Cl- channels, we measured the rate of 125-Iodide (125I-) efflux to assay Cl- channel activity in intact cells and examined cell-free membrane patches from cultured canine tracheal epithelial cells. The Ca2+ elevating agonist bradykinin and the calcium ionophore A23187 increased 125I- efflux. This response did not require prostaglandin production. Under several conditions, changes in [Ca2+]c were temporally dissociated from changes in channel activation: a transient increase in [Ca2+]c caused a prolonged stimulation of 125I- efflux. Neither Cl- channel activation nor open-channel probability was affected by varying internal [Ca2+] in excised membrane patches. Adenosine 3',5'-cyclic monophosphate (cAMP)- and Ca2(+)-dependent channel activation may be independent: cAMP-stimulated 125I- efflux did not require an increase in [Ca2+]c, Ca2(+)-stimulated efflux did not require an increase in cAMP, and simultaneous addition of A23187 and isoproterenol produced additive effects on 125I- efflux. The data suggest that an increase in [Ca2+]c activates Cl- channels, however, the effect of Ca2+ appears to be indirect, not involving a ligand-type interaction with the channel.
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Schultz, B. D., A. D. DeRoos, C. J. Venglarik, A. K. Singh, R. A. Frizzell, and R. J. Bridges. "Glibenclamide blockade of CFTR chloride channels." American Journal of Physiology-Lung Cellular and Molecular Physiology 271, no. 2 (August 1, 1996): L192—L200. http://dx.doi.org/10.1152/ajplung.1996.271.2.l192.
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The cystic fibrosis transmembrane conductance regulator (CFTR) is a protein kinase A- and ATP-regulated Cl- channel located in the apical membranes of epithelial cells. Previously Sheppard and Welsh (J. Gen. Physiol. 100: 573-591, 1992) showed that glibenclamide, a compound which binds to the sulfonylurea receptor and thus blocks nucleotide-dependent K+ channels, reduced CFTR whole cell current. The aim of this study was to identify the mechanism underlying this inhibition in cell-free membrane patches containing CFTR Cl- channels. Exposure to gliben-clamide caused a reversible reduction in current carried by CFTR which was paralleled by a decrease in channel open probability (Po). The decrease in Po was concentration dependent, and half-maximum inhibition (ki) occurred at 30 microM. Fluctuation analysis indicated a flickery-type block of open CFTR channels. Event duration analysis supported this notion by showing that the glibenclamide-induced decrease in Po was accompanied by interruptions of open bursts [i.e., an apparent reduction in the burst duration (Tburst)] with only a slight reduction in closed time (Tc). The plot of the corresponding open-to-closed (Tburst-1) and closed-to-open (Tc-1) rates as a function of glibenclamide concentration were consistent with a pseudo-first-order open-blocked mechanism and provided estimates of the on rate (kon = 1.17 microM-1S-1), the off rate (koff = 16 s-1), and the dissociation constant (Kd = 14 microM). The difference between the Ki (30 microM) and the Kd (14 microM) is the result expected for a closed-open-blocked model with an initial Po of 0.47. Since the initial Po was 0.50 +/- 0.02 (n = 12), we can conclude that glibenclamide blocks CFTR by a closed-open-blocked mechanism.
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Elorza-Vidal, Xabier, Héctor Gaitán-Peñas, and Raúl Estévez. "Chloride Channels in Astrocytes: Structure, Roles in Brain Homeostasis and Implications in Disease." International Journal of Molecular Sciences 20, no. 5 (February 27, 2019): 1034. http://dx.doi.org/10.3390/ijms20051034.
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Astrocytes are the most abundant cell type in the CNS (central nervous system). They exert multiple functions during development and in the adult CNS that are essential for brain homeostasis. Both cation and anion channel activities have been identified in astrocytes and it is believed that they play key roles in astrocyte function. Whereas the proteins and the physiological roles assigned to cation channels are becoming very clear, the study of astrocytic chloride channels is in its early stages. In recent years, we have moved from the identification of chloride channel activities present in astrocyte primary culture to the identification of the proteins involved in these activities, the determination of their 3D structure and attempts to gain insights about their physiological role. Here, we review the recent findings related to the main chloride channels identified in astrocytes: the voltage-dependent ClC-2, the calcium-activated bestrophin, the volume-activated VRAC (volume-regulated anion channel) and the stress-activated Maxi-Cl−. We discuss key aspects of channel biophysics and structure with a focus on their role in glial physiology and human disease.
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Vaisey, George, Alexandria N. Miller, and Stephen B. Long. "Distinct regions that control ion selectivity and calcium-dependent activation in the bestrophin ion channel." Proceedings of the National Academy of Sciences 113, no. 47 (November 7, 2016): E7399—E7408. http://dx.doi.org/10.1073/pnas.1614688113.
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Cytoplasmic calcium (Ca2+) activates the bestrophin anion channel, allowing chloride ions to flow down their electrochemical gradient. Mutations in bestrophin 1 (BEST1) cause macular degenerative disorders. Previously, we determined an X-ray structure of chicken BEST1 that revealed the architecture of the channel. Here, we present electrophysiological studies of purified wild-type and mutant BEST1 channels and an X-ray structure of a Ca2+-independent mutant. From these experiments, we identify regions of BEST1 responsible for Ca2+ activation and ion selectivity. A “Ca2+ clasp” within the channel’s intracellular region acts as a sensor of cytoplasmic Ca2+. Alanine substitutions within a hydrophobic “neck” of the pore, which widen it, cause the channel to be constitutively active, irrespective of Ca2+. We conclude that the primary function of the neck is as a “gate” that controls chloride permeation in a Ca2+-dependent manner. In contrast to what others have proposed, we find that the neck is not a major contributor to the channel’s ion selectivity. We find that mutation of a cytosolic “aperture” of the pore does not perturb the Ca2+ dependence of the channel or its preference for anions over cations, but its mutation dramatically alters relative permeabilities among anions. The data suggest that the aperture functions as a size-selective filter that permits the passage of small entities such as partially dehydrated chloride ions while excluding larger molecules such as amino acids. Thus, unlike ion channels that have a single “selectivity filter,” in bestrophin, distinct regions of the pore govern anion-vs.-cation selectivity and the relative permeabilities among anions.
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Kolesnikov, D. O., E. R. Grigorieva, M. A. Nomerovskaya, D. S. Reshetin, A. V. Shalygin, and E. V. Kaznacheyeva. "The Mechanism of Calcium-Activated Chloride ANO6 Channel Inhibition by CaCCinh-A01." Биологические мембраны Журнал мембранной и клеточной биологии 41, no. 2 (June 14, 2024): 133–38. http://dx.doi.org/10.31857/s0233475524020046.
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Proteins of the anoctamine family (ANO) form calcium-activated chloride channels (CaCC) and phospholilpid scramblases. The ANO6 (TMEM16F) protein, which combines the functions of a calcium-dependent scramblase and those of an ion channel, is considered as a molecular target for the treatment of blood clotting disorders, COVID-19-associated pneumonia, neurodegenerative diseases, and other pathologies. CaCCinh-A01, which is a channel blocker of the ANO family, is studied as a potential pharmacological drug. Previously, the effect of this inhibitor was studied using methods representing the integral ion current through the membrane, which does not allow the properties of single channels to be distinguished. Therefore, it remains unknown which characteristics of single channels are sensitive to the blocker: channel open probability, the current amplitude, or the dwelling time of the channel open state. By registration of single ANO6 channels in HEK293 cells, we showed that the action of the inhibitor is due to a decrease in both the current amplitude and the open state dwelling time of single ANO6 channels, which, in turn, leads to a decrease in their open state probability. Thus, we have characterized the mechanism of current reduction through ANO6 channels by the inhibitor CaCCinh A01.
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Wang, Liwei, Wenbo Ma, Linyan Zhu, Dong Ye, Yuan Li, Shanwen Liu, Huarong Li, et al. "ClC-3 is a candidate of the channel proteins mediating acid-activated chloride currents in nasopharyngeal carcinoma cells." American Journal of Physiology-Cell Physiology 303, no. 1 (July 1, 2012): C14—C23. http://dx.doi.org/10.1152/ajpcell.00145.2011.
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Acid-activated chloride currents have been reported in several cell types and may play important roles in regulation of cell function. However, the molecular identities of the channels that mediate the currents are not defined. In this study, activation of the acid-induced chloride current and the possible candidates of the acid-activated chloride channel were investigated in human nasopharyngeal carcinoma cells (CNE-2Z). A chloride current was activated when extracellular pH was reduced to 6.6 from 7.4. However, a further decrease of extracellular pH to 5.8 inhibited the current. The current was weakly outward-rectified and was suppressed by hypertonicity-induced cell shrinkage and by the chloride channel blockers 5-nitro-2–3-phenylpropylamino benzoic acid (NPPB), tamoxifen, and 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid disodium salt hydrate (DIDS). The permeability sequence of the channel to anions was I− > Br− > Cl− > gluconate−. Among the ClC chloride channels, ClC-3 and ClC-7 were strongly expressed in CNE-2Z cells. Knockdown of ClC-3 expression with ClC-3 small interfering (si)RNA prevented the activation of the acid-induced current, but silence of ClC-7 expression with ClC-7 siRNA did not significantly affect the current. The results suggest that the chloride channel mediating the acid-induced chloride current was volume sensitive. ClC-3 is a candidate of the channel proteins that mediate or regulate the acid-activated chloride current in nasopharyngeal carcinoma cells.
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Berndt, Andre, Soo Yeun Lee, Jonas Wietek, Charu Ramakrishnan, Elizabeth E. Steinberg, Asim J. Rashid, Hoseok Kim, et al. "Structural foundations of optogenetics: Determinants of channelrhodopsin ion selectivity." Proceedings of the National Academy of Sciences 113, no. 4 (December 22, 2015): 822–29. http://dx.doi.org/10.1073/pnas.1523341113.
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The structure-guided design of chloride-conducting channelrhodopsins has illuminated mechanisms underlying ion selectivity of this remarkable family of light-activated ion channels. The first generation of chloride-conducting channelrhodopsins, guided in part by development of a structure-informed electrostatic model for pore selectivity, included both the introduction of amino acids with positively charged side chains into the ion conduction pathway and the removal of residues hypothesized to support negatively charged binding sites for cations. Engineered channels indeed became chloride selective, reversing near −65 mV and enabling a new kind of optogenetic inhibition; however, these first-generation chloride-conducting channels displayed small photocurrents and were not tested for optogenetic inhibition of behavior. Here we report the validation and further development of the channelrhodopsin pore model via crystal structure-guided engineering of next-generation light-activated chloride channels (iC++) and a bistable variant (SwiChR++) with net photocurrents increased more than 15-fold under physiological conditions, reversal potential further decreased by another ∼15 mV, inhibition of spiking faithfully tracking chloride gradients and intrinsic cell properties, strong expression in vivo, and the initial microbial opsin channel-inhibitor–based control of freely moving behavior. We further show that inhibition by light-gated chloride channels is mediated mainly by shunting effects, which exert optogenetic control much more efficiently than the hyperpolarization induced by light-activated chloride pumps. The design and functional features of these next-generation chloride-conducting channelrhodopsins provide both chronic and acute timescale tools for reversible optogenetic inhibition, confirm fundamental predictions of the ion selectivity model, and further elucidate electrostatic and steric structure–function relationships of the light-gated pore.
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Tsai, L. M., M. Dillard, R. L. Rosenberg, R. J. Falk, M. L. Gaido, and A. L. Finn. "Reconstitution of an epithelial chloride channel. Conservation of the channel from mudpuppy to man." Journal of General Physiology 98, no. 4 (October 1, 1991): 723–50. http://dx.doi.org/10.1085/jgp.98.4.723.
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We have previously shown that monoclonal antibody E12 (MAb E12), one of several such antibodies raised against theophylline-treated Necturus gallbladder (NGB) epithelial cells, inhibits the chloride conductance in the apical membrane of that tissue. Since chloride channels are critical to the secretory function of epithelia in many different animals, we have used this antibody to determine whether the channels are conserved, and in an immunoaffinity column to isolate the channel protein. We now demonstrate that MAb E12 cross-reacts with detergent-solubilized extracts of different tissues from various species by enzyme-linked immunosorbent assay (ELISA). Western blot analysis shows that this monoclonal antibody recognizes proteins of Mr 219,000 in NGB, toad gallbladder, urinary bladder, and small intestine, A6 cells, rat colon, rabbit gastric mucosa, human lymphocytes, and human nasal epithelial cells, and inhibits the chloride conductance in toad gallbladder, rat colon, and human nasal epithelium. Detergent-solubilized protein eluted from an immunoaffinity column and then further purified via FPLC yields a fraction (Mr 200,000-220,000) which has been reconstituted into a planar lipid bilayer. There it behaves as a chloride-selective channel (PCl/PNa = 20.2 in a 150/50 mM trans-bilayer NaCl gradient) whose unit conductance is 62.4 +/- 4.6 pS, and which is blocked in the bilayer by the antibody. The gating characteristics of this channel indicate that it can exist as aggregates or as independent single channels, and that the antibody interferes with gating of the aggregates, leaving the unit channels unchanged. From these data we conclude that the protein of Mr 219,000 recognized by this monoclonal antibody is an important component of an epithelial chloride channel, and that this channel is conserved across a wide range of animal species.
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Sonnhof, U. "Single voltage-dependent K+ and Cl− channels in cultured rat astrocytes." Canadian Journal of Physiology and Pharmacology 65, no. 5 (May 1, 1987): 1043–50. http://dx.doi.org/10.1139/y87-165.
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The kinetic reactions of a voltage-dependent K+ channel, which constituted about 14% of all the recorded K+ channels in the membrane of cultured rat astrocytes were studied in detail. A scheme of one open and three closed states is necessary to describe the kinetic reactions of this channel. The channel contributes little to the resting membrane potential. Its steady state open probability (Po) is 0.06 at −70 mV. When the cell is depolarized to 0 mV, Po approaches 1. This represents a 17-fold increase. Such channels could contribute to the potassium clearance by enhancing the effect of "spatial buffering." Additionally, single anion-selective channels with very high conductances were found in inside-out patches in approximately 15% of all recorded channels in the membrane of rat astrocytes. Channel openings are characterized by more than one conductance level; the main level showed a mean conductance of 400 pS. These channels are divided into two groups. Approximately 90% of the recorded chloride channels showed a strong voltage dependency of their current fluctuations. Within a relatively small potential range (±15 mV) the channels have a high probability of being in the active state. After a voltage jump to varying testing potentials in the range of ±20 to ±50 mV the channels continued to be in the active state for some time and then closed to a shut state. If the testing potential persisted, the channels were not able to leave this shut state. The active state could only be reached again if the membrane potential was reset close to zero for some time. The time course of the current relaxation was measured by ensemble averaging of single channel current fluctuations. When at the end of a testing potential the voltage was set back to zero, the channel remained in the shut state for some time before it reached the open state again. The voltage dependence of this recovery period was analyzed as well but is not shown in this paper. The reaction indicates a nonstationary process as the open probability is time dependent, and for better differentiation I will call these channels nonstationary chloride channels. A subgroup of 10% of all recorded chloride channels showed no voltage-dependent kinetic reactions. I will denote them as stationary chloride channels. Both types of Cl− channels are mainly permeable to anions but showed a slight permeability to cations. An idea of the role of these channels at this state must be highly speculative. The possibilities include a cell to cell transfer of material or a regulation of the internal or external ion environment. In the latter case, they could provide an uptake mechanism for potassium ions in addition to the spatial buffer currents.
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Zhu, Yaohui, Andrea Mucci, and Jan D. Huizinga. "Inwardly rectifying chloride channel activity in intestinal pacemaker cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 288, no. 4 (April 2005): G809—G821. http://dx.doi.org/10.1152/ajpgi.00301.2004.
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Cl− channels are proposed to play a role in gut pacemaker activity, but little is known about the characteristics of Cl− channels in interstitial cells of Cajal (ICC), the intestinal pacemaker cells. The objective of the present study was to identify whole cell Cl− currents in ICC associated with previously observed single-channel activity and to characterize its inward rectification. Whole cell patch-clamp studies showed that ICC express an inwardly rectifying Cl− current that was not sensitive to changes in cation composition of the extracellular solutions. Currents were not affected by replacing all cations with N-methyl-d-glucamine (NMDG+). Whole cell currents followed the Cl− equilibrium potential and were inhibited by DIDS and 9-anthracene carboxylic acid. Ramp protocols of single-channel activity showed that inward rectification was due to reduction in single-channel open probability, not a reduction in single-channel conductance. Single-channel data led to the hypothesis that strong cooperation exists between 30-pS channels that show less cooperation at potentials positive to the reversal potential. Hence, an inwardly rectifying Cl− channel plays a prominent role in determining pacemaker activity in the gut.
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Hao, Feng, Zhong Hai Yuan, Zhi Xin Wang, Hui Jing Xu, Fang Fang, Xin Gang Guan, Jiang Yong, and Li Yan. "Plasmid Construction of TMEM16A-pcDNA3.1 and its Application to Transient and Stable Transfection of FRT Cells." Advanced Materials Research 554-556 (July 2012): 1734–37. http://dx.doi.org/10.4028/www.scientific.net/amr.554-556.1734.
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Calcium-activated chloride channels (CaCCs) play pivotal roles in many physiological Activities, including transepithelial fluid secretion, smooth muscle contraction and sensory transduction. TMEM16A is a bona fide calcium-activated chloride channel，which was discovered by three independent labs in 2008 after Calcium-activated chloride channel current was recorded about thirty years ago. In this study, DNA fragments encoding mouse TMEM16A with green fluorescence protein (GFP) fusion protein were subcloned into pcDNA3.1/Zeo. Transient transfection condition was optimized and Fischer Thyroid epithelial cells (FRT) expressing TMEM16A were got by stable transfection. The classical calcium-activated chloride channels current was recorded in FRT cells stably expressing TMEM16A by whole cell patch clamp technique. These results were beneficial for the delving into the effects of other bivalent cations on TMEM16A-CaCCs and the role of TMEM16A-CaCCs in cell proliferation and migration.
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Jentsch, Thomas J., Valentin Stein, Frank Weinreich, and Anselm A. Zdebik. "Molecular Structure and Physiological Function of Chloride Channels." Physiological Reviews 82, no. 2 (April 1, 2002): 503–68. http://dx.doi.org/10.1152/physrev.00029.2001.
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Cl− channels reside both in the plasma membrane and in intracellular organelles. Their functions range from ion homeostasis to cell volume regulation, transepithelial transport, and regulation of electrical excitability. Their physiological roles are impressively illustrated by various inherited diseases and knock-out mouse models. Thus the loss of distinct Cl− channels leads to an impairment of transepithelial transport in cystic fibrosis and Bartter's syndrome, to increased muscle excitability in myotonia congenita, to reduced endosomal acidification and impaired endocytosis in Dent's disease, and to impaired extracellular acidification by osteoclasts and osteopetrosis. The disruption of several Cl− channels in mice results in blindness. Several classes of Cl− channels have not yet been identified at the molecular level. Three molecularly distinct Cl− channel families (CLC, CFTR, and ligand-gated GABA and glycine receptors) are well established. Mutagenesis and functional studies have yielded considerable insights into their structure and function. Recently, the detailed structure of bacterial CLC proteins was determined by X-ray analysis of three-dimensional crystals. Nonetheless, they are less well understood than cation channels and show remarkably different biophysical and structural properties. Other gene families (CLIC or CLCA) were also reported to encode Cl− channels but are less well characterized. This review focuses on molecularly identified Cl− channels and their physiological roles.
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WALDEGGER, SIEGFRIED, and THOMAS J. JENTSCH. "From Tonus to Tonicity." Journal of the American Society of Nephrology 11, no. 7 (July 2000): 1331–39. http://dx.doi.org/10.1681/asn.v1171331.
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Abstract. Chloride channels are involved in a multitude of physiologic processes ranging from basal cellular functions such as cell volume regulation and acidification of intracellular vesicles to more specialized mechanisms such as vectorial transepithelial transport and regulation of cellular excitability. This plethora of functions is accomplished by numerous functionally highly diverse chloride channels that are only partially identified at the molecular level. The CLC family of chloride channels comprises at present nine members in mammals that differ with respect to biophysical properties, cellular compartmentalization, and tissue distribution. Their common structural features include a predicted topology model with 10 to 12 transmembrane regions together with two C-terminal CBS domains. Loss of function mutations affecting three different members of the CLC channel family lead to three human inherited diseases : myotonia congenita, Dent's disease, and Bartter's syndrome. These diseases, together with the diabetes insipidus symptoms of a knockout mouse model, emphasize the physiologic relevance of this ion channel family.
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BUYSE, Gunnar, Dominique TROUET, Thomas VOETS, Ludwig MISSIAEN, Guy DROOGMANS, Bernd NILIUS, and Jan EGGERMONT. "Evidence for the intracellular location of chloride channel (ClC)-type proteins: co-localization of ClC-6a and ClC-6c with the sarco/endoplasmic-reticulum Ca2+ pump SERCA2b." Biochemical Journal 330, no. 2 (March 1, 1998): 1015–21. http://dx.doi.org/10.1042/bj3301015.
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Chloride channel protein (ClC)-6a and ClC-6c, a kidney-specific splice variant with a truncated C-terminus, are proteins that belong structurally to the family of voltage-dependent chloride channels. Attempts to characterize functionally ClC-6a or ClC-6c in Xenopus oocytes have so far been negative. Similarly, expression of both ClC-6 isoforms in mammalian cells failed to provide functional information. One possible explanation of these negative results is that ClC-6 is an intracellular chloride channel rather than being located in the plasma membrane. We therefore studied the subcellular location of ClC-6 isoforms by transiently transfecting COS and CHO cells with epitope-tagged versions of ClC-6a and ClC-6c. Confocal imaging of transfected cells revealed for both ClC-6 isoforms an intracellular distribution pattern that clearly differed from the peripheral location of CD2, a plasma-membrane glycoprotein. Furthermore, dual-labelling experiments of COS cells co-transfected with ClC-6a or -6c and the sarco/endoplasmic-reticulum Ca2+ pump (SERCA2b) indicated that the ClC-6 isoforms co-localized with the SERCA2b Ca2+ pump. Thus ClC-6a and ClC-6c are intracellular membrane proteins, most likely residing in the endoplasmic reticulum. In view of their structural similarity to proven chloride channels, ClC-6 isoforms are molecular candidates for intracellular chloride channels.
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Narahashi, T., X. Zhao, T. Ikeda, K. Nagata, and JZ Yeh. "Differential actions of insecticides on target sites: basis for selective toxicity." Human & Experimental Toxicology 26, no. 4 (April 2007): 361–66. http://dx.doi.org/10.1177/0960327106078408.
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Whereas the selective toxicity of insecticides between insects and mammals has a long history of studies, it is now becoming abundantly clear that, in many cases, the differential action of insecticides on insects and mammalian target receptor sites is an important factor. In this paper, we first introduce the mechanism of action and the selective toxicity of pyrethroids as a prototype of study. Then, a more detailed account is given for fipronil, based primarily on our recent studies. Pyrethroids keep the sodium channels open for a prolonged period of time, causing elevation of the depolarizing after-potential. Once the after-potential reaches the threshold for excitation, repetitive after-discharges are produced, resulting in hyperexcitation of intoxicated animals. Only about 1% of sodium channels needs to be modified to produce hyperexcitation, indicating a high degree of toxicity amplification from sodium channels to animals. Pyrethroids were >1000-fold more potent on cockroach sodium channels than rat sodium channels, and this forms the most significant factor to explain the selective toxicity of pyrethroids in insects over mammals. Fipronil, a phenylpyrazole, is known to act on the γ-aminobutyric acid receptor to block the chloride channel. It is effective against certain species of insects that have become resistant to most insecticides, including those acting on the γ-aminobutyric acid receptor, and is much more toxic to insects than to mammals. Recently, fipronil has been found to block glutamate-activated chloride channels in cockroach neurons in a potent manner. Since mammals are devoid of this type of chloride channel, fipronil block of the glutamate-activated chloride channel is deemed responsible, at least partially, for the higher selective toxicity to insects over mammals and for the lack of cross-resistance. Human & Experimental Toxicology (2007) 26, 361-366