chloride channels

..and mammals and activity against dieldrin-resistant insects, we studied fipronil action on glutamate-gated chloride channels (GluCls), unique invertebrate ligand-gated chloride channels, in cockroach thoracic ganglion neurons, using ..

..Comparison with prokaryotic CLC shows that a gating glutamate residue changes conformation and suggests a basis for 2:1 Cl(-)/H(+) exchange and a simple mechanistic connection between CLC channels and transporters...

Calcium-dependent chloride channels are required for normal electrolyte and fluid secretion, olfactory perception, and neuronal and smooth muscle excitability. The molecular identity of these membrane proteins is still unclear...

..The genotype-phenotype correlations that are observed in association with BEST1 mutations are discussed. In addition, in vitro studies and animal models that clarify the pathophysiological mechanisms are reviewed...

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Calcium-activated chloride channels (CaCCs) are major regulators of sensory transduction, epithelial secretion, and smooth muscle contraction...

..Molecular identification of VSOR is required to address the question of how cells sense volume expansion and activate VSOR...

..To analyze functional and clinical data of Best vitelliform macular dystrophy (VMD) patients with mutations in the BEST1 gene...

..GluCl provides a framework for understanding mechanisms of fast inhibitory neurotransmission and allosteric modulation of Cys-loop receptors...

..Bestrophins are also regulated by cell volume and may be a member of the volume-regulated anion channel family...

Calcium (Ca(2+))-activated chloride channels are fundamental mediators in numerous physiological processes including transepithelial secretion, cardiac and neuronal excitation, sensory transduction, smooth muscle contraction and ..

..L140V and p.D228N) caused mislocalization of bestrophin-1 from the basolateral membrane to the cytoplasm. Mutations in bestrophin-1 are increasingly recognized as an important cause of inherited retinal dystrophy...

..Immunohistochemistry of skeletal muscle from ADR and other mouse models of human muscle disease demonstrate that the absence of ClC-1 chloride channel is a defect specific to ADR mice...

..There were no mutations found in the AMD group. In addition, four frequent intragenic polymorphisms did not reveal allelic association of the VMD2 locus with AMD. These data exclude a direct role of VMD2 in the predisposition to AMD...

..To characterize the phenotype of members of a Swedish family with Best macular dystrophy and two distinct mutations in VMD2...

Members of the CLC gene family either function as chloride channels or as anion/proton exchangers. The plant AtClC-a uses the pH gradient across the vacuolar membrane to accumulate the nutrient NO(3)(-) in this organelle...

..To report 11 cases of autosomal recessive vitelliform macular dystrophy and to compare their molecular findings and phenotypic characteristics with those of patients with the more common and well-described dominant form of the disease...

..For the first time, high-resolution imaging provided in vivo evidence of RPE and photoreceptor involvement in ARB...

..This study shows that TMEM16A expression is robust in murine vascular smooth muscle cells, consolidating the view that this gene is a viable candidate for the native Ca(2+)-activated Cl(-) channel in this cell type...

..The purpose of this study was to investigate the BEST1 gene mutations in Chinese patients with Best vitelliform macular dystrophy (BVMD)...

..The potency of these agents indicates that compounds in this class may be of therapeutic benefit in CFTR-related diseases, including cystic fibrosis...

..To examine the clinical phenotype of three Swedish families with Best's vitelliform macular dystrophy (BMD) and three different mutations in the recently identified bestrophin gene...

Nematode glutamate-gated chloride channels are targets of the macrocyclic lactones, the most important group of anthelmintics available...

..To describe clinical and genetic findings in an Italian family affected by Best disease...

..5. The present study shows that regulation of Ca(2+)-dependent Cl(-) channels by CaMKII differs between arterial and portal vein myocytes...

..To characterize the outward chloride currents (Cl(OR)) in single acinar cells isolated from the rabbit superior lacrimal gland (RSLG) to investigate the hypothesis that Cl(OR) may have a role in regulating the volume of RSLG acini...

..Some members of this family are up-regulated in a number of tumours and functional deficiency in others is linked to developmental defects...

..We propose that a transdominant effect of mutant RNA on RNA processing leads to chloride channelopathy and membrane hyperexcitability in DM...

..Expression of glc-3 cRNA in XENOPUS oocytes resulted in the formation of homo-oligomeric L-glutamate-gated chloride channels with robust and rapidly desensitizing currents, an EC(50) of 1.9+/-0.03 mM and a Hill coefficient of 1.5+/-0...

..Finally, we have evidence that some mutations are associated with variable expression of the disease, suggesting the involvement of other factors or genes in the disease phenotype...

..These findings indicate that genetic CLC-1 deficiency not only affects muscle relaxation (myotonia) but also modulates diaphragm performance during the contractile phase of the contraction-relaxation cycle...

..that the avermectin/milbemycin family of anthelmintics act via specific interactions with glutamate-gated chloride channels. These channels are encoded by a small family of genes in nematodes, though the composition of the gene ..

..This review discusses the proposed roles of abnormal Cl(-) channel activity in the pathogenesis of human diseases...

..To describe morphological and functional changes in a single patient with multifocal Best vitelliform macular dystrophy (BVMD) and to perform a genotype/phenotype correlation...

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..Finally, the changes we observe in the granules suggest that the histopathology and eventual vision loss associated with BMD may be due to defects in the ability of the RPE to fully degrade phagocytosed photoreceptor outer segments...

..The compartmentalized localization and the electrophysiological properties suggest TMEM16B to be a strong candidate for the long sought-after Ca(2+)-dependent chloride channel in the photoreceptor synapse...

..When the t-system chloride conductance was eliminated, either by removal of all Cl(-) or by block of the chloride channels with 9-anthracene carboxylic acid (9-AC) or by treating muscles with phorbol 12,13-dibutyrate, there was a ..

..The nature of the vitelliform material and the reason the development of such lesions is usually restricted to the macula are two unsolved questions in the pathogenesis of this disorder...

b>Chloride channels represent a relatively under-explored target class for drug discovery as elucidation of their identity and physiological roles has lagged behind that of many other drug targets...

..I conclude that investigation of the tweety family will provide important information about large-conductance Cl- channel molecules...

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..These results implicate chloride ion channels in muscle function and emphasize that intracellular acidosis of muscle has protective effects during muscle fatigue...

..Our results support the hypothesis that manifestations of DM can result from sequestration of specific RNA binding proteins by a repetitive element expansion in a mutant RNA...

..We conclude that each tissue expresses a set of anoctamins that form cell- and tissue-specific Ca(2+)-dependent Cl(-) channels...

..Niflumic acid (in the presence of 4-AP) leads to prolongation of the early repolarization. Thus this current may contribute to early repolarization of action potentials in mouse ventricular myocytes...

..Maximal physiological Cl(-) secretion occurs only for synergistic activation mechanisms that close these basolateral membrane Cl(-) channels...

..ClC-5 might facilitate endosome trafficking in the epididymis, as has been proposed in the kidney...

..These results suggest that NFA and DCDPC, but not DIDS, simultaneously enhance and block I(Cl(Ca)) by binding to an external site, probably close to the mouth of the chloride channel...

..These data suggest that Cl(-) flux through ion channels rather than transporters is essential for volume regulation of cultured astrocytes in response to hypotonic challenge...

..We conclude that hCLCA1 and mCLCA3 are non-integral membrane proteins and therefore cannot be chloride channels in their own right.

..We provide the first experimental investigation of structural changes resulting from myotonia-causing mutations...

..expression system rather than the CLCA protein suggests that these proteins are not independent Ca2+-dependent chloride channels, but may contribute to the activity of chloride channels formed by, or in conjunction with, other proteins.

..Finally, we identified several candidate proteins that may be involved in RVD, including the Cl(-) channels ClC-2, ClC-3, ClC-5, ClC-6, and ClC-7 and the transporters KCC1 and KCC3a...

..048 ). These results demonstrate that a GluCl agonist enhances IVM activity and provides further information on the mode of action of ivermectin in parasitic nematodes...

..Thus, interactions of permeant anions with these two sites hinder the closing mechanism and stabilize the channel in the open state...

..In accordance with our patch-clamp data, osmotic swelling increases activity of immunoprecipitated p56lck. We conclude that osmotic swelling activates ICl-swell in lymphocytes via the tyrosine kinase p56lck...

Rodent ClC-K1 and ClC-K2, and their respective human orthologs ClCKA and ClCKB, are chloride channels specific to the kidney (and inner ear); Barttin is their functionally important subunit...

..A disturbed interaction reduces the currents of the Ca(V)1.3 subunits. This mechanism could open new ways to understand changes in the patient's electro-oculogram and functional alterations of the RPE leading to retinal degeneration...

..This provides further evidence for an allosteric mechanism of picrotoxin inhibition, but renders it unlikely that picrotoxin (as an allosterically acting 'competitive' antagonist) binds to this residue...

..Our data suggest that TMEM16A CaCC-mediated Cl(-) secretion appears to be necessary for normal airway surface liquid homeostasis...

..The roles of the other TMEM16 proteins are still unknown. The study of TMEM16 proteins may lead to identification of novel molecular mechanisms underlying ion transport and channel gating by voltage and Ca(2+)...

..Therefore, the contribution of Cl- currents to the genesis of arrhythmias may depend on their association with the conductance of other ions, especially that of K+...

..These findings are consistent with a model in which CLC5 encodes an endosomal chloride channel that facilitates acidification and trafficking of renal epithelial endosomes...

..We have identified in the nematode Caenorhabditis elegans three ligand-gated chloride channels that are receptors for biogenic amines: LGC-53 is a high-affinity dopamine receptor, LGC-55 is a high-..

..Our results demonstrate that mTMEM16B functions as a Ca(2+)-activated Cl(-) channel when expressed in HEK 293T cells...

..We speculate that during sustained membrane depolarization, calcium influx activates ICLCA which functions to modulate NaCl transport across the apical membrane of IMCD cells...

..Recently, a novel gene family encoding voltage-gated chloride channels, the ClC family, was identified...

..The findings support alpha-AP-2 in directing myosin VI-dependent endocytosis of CFTR and a requirement for myosin VI in membrane invagination and coated pit formation in enterocytes...

..frame encodes 760 amino acids, which possess significantly amino acid identity with previously cloned CIC chloride channels. The chloride currents expressed in Xenopus oocytes injected with CIC-3 cRNA were completely blocked by ..

..To describe genetic and clinical findings in a French family affected by best vitelliform macular dystrophy (BVMD)...

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..Thus, a single functional architecture serves two entirely different purposes, probably underscoring the epithelial origin of the ORNs...

..In the closed conformation of the channel, a conserved glutamate residue occupies one of the ion-binding sites; on channel opening, this glutamate residue moves out of the binding site, thereby making room for an additional Cl(-) ion...

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..This information will be useful in understanding the mechanisms controlling aqueous humor formation and thereby intraocular pressure...

..The BK-evoked Cl(-) conductance in NGNs may be the first demonstration of an inflammatory mediator exciting primary afferents via an anion channel...

..Together, these studies demonstrate that SPI-0211 is a potent activator of ClC-2 Cl- channels and suggest a physiologically relevant role for ClC-2 Cl- channels in intestinal Cl- transport after SPI-0211 administration...

..Thus, quercetin induces Cl- secretion merely by activation of K+ channels in the colon epithelium...

..To assess the impact of these and other chloride-dependent mechanisms on release from cones, the chloride equilibrium potential (ECl) was determined in red-sensitive, large single cones from the tiger salamander retinal slice...

..The present study is the first to characterize the VACC in mouse cholangiocyte and will provide an important framework for further studies to examine and understand the role of the VACC in biliary secretion and ion-transport physiology...

..In isometric tension recordings, NFA inhibited spontaneous contractions. These data support a role for this conductance in portal vein excitability...

..These results suggest that small intestinal crypt cells express multiple types of Cl- channels, which may all contribute to net Cl- secretion...

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Eukaryotic members of the CLC gene family function as plasma membrane chloride channels, or may provide neutralizing anion currents for V-type H(+)-ATPases that acidify compartments of the endosomal/lysosomal pathway...

Calcium-activated chloride channels (CaCCs) are widely expressed in mammalian tissues, including intestinal epithelia, where they facilitate fluid secretion. Potent, selective CaCC inhibitors have not been available...

..Such a variability in [Cl(-)](i) may be one of the reasons for the variations in the ACh-induced membrane response...

..Sensitization was transient in response to neuron activity. In the silent neuron, sensitization of gCl shifted membrane potential over a range of about 15 mV...

..These data show how to unravel the CNG and Ca(2+)-activated Cl(-) component of the current rising phase...

..These data confirm that ClC-3 is important in VRAC function and cell volume regulation, is associated with the I(Cl,LPA) current activity, and participates in the fibroblast-to-myofibroblast transition...

..This chapter is an overview of selective studies on the newly discovered roles of GlyRs in regulating neuronal excitation, and inhibition, particularly in the upper brain areas...

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..These results demonstrate that three types of functional ion channel currents (i.e., I(Kir), I(KCa), and I(Cl)) are present in mouse bone marrow MSCs...

..These data suggest that PMC is an integral part of cell division and is dependent on ClC3 channel function...

..A possible physiological role for a divalent metal ion receptor, distinct from the extracellular Ca(2+)-sensing receptor, in IMCD cells is discussed...

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..This association may have important pathophysiological consequences, enabling increased ClC-2 activity in response to cellular stresses such as elevated temperature, ischemia, or oxidative reagents...

..In conclusion, swelling or volume change will depolarize ICC through activation of outwardly rectifying chloride channels, thereby increasing cell excitability.

..Our findings contribute to a growing body of evidence indicating that cytoplasmic domains play key roles in the gating and regulation of eukaryotic ClCs...

An inhibitory role of strychnine-sensitive glycine-gated chloride channels (GlyRs) in the brain has largely been ignored, despite the known expression of these receptors throughout the CNS...

..The following studies will examine the role of these lipids in exacerbating the symptoms of Cystic fibrosis and will be used in developing new therapeutic approaches for this disease. ..

b>Chloride channels and transporters of the CLC family play crucial roles in a myriad of physiological processes including regulation of electrical excitability of nerve and muscle cells, modulation of salt and water movement across ..

b>Chloride channels and transporters of the CLC family play crucial roles in a myriad of physiological processes including regulation of electrical excitability of nerve and muscle cells, modulation of salt and water movement across ..

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..The studies to be pursued in this grant combine the promising novel approach of oncolytic virotherapy with the use of radioactive iodine for the treatment of this disease. ..

..Furthermore, we aim to identify the suitability of genistein as a potential therapeutic for the most common lethal genetic disease in Caucasians, cystic fibrosis (CF). ..

..Specific Aim #3 will test the hypothesis that chloride channels contribute to regulation of membrane potential in cerebral arteries...

..The information obtained from this study should provide an opportunity to formulate superior therapeutic approaches in chronic asthma. ..

..anion secretion in the intestine. The additional funds provided by this award will enable the PI to expand investigations and develop collaborations as she pursues these revised specific aims. ..

..In the proposed studies, we are examining the cell surface stability of this chloride channel and the cellular mechanisms that regulate its cell surface stability. ..

..In the proposed studies, we are examining the cell surface stability of this chloride channel and the cellular mechanisms that regulate its cell surface stability. ..

..Understanding these processes are important in understanding the cellular basis for a number of lung pathologies including cystic fibrosis and chronic obstructive pulmonary disease (COPD). ..

..Understanding these processes are important in understanding the cellular basis for a number of lung pathologies including cystic fibrosis and chronic obstructive pulmonary disease (COPD). ..

..Translational opportunities that may arise from this work include modulating CFTR expression in vivo and the construction of efficient, tissue-specific gene therapy vectors. ..

..Translational opportunities that may arise from this work include modulating CFTR expression in vivo and the construction of efficient, tissue-specific gene therapy vectors. ..

..The genetics and molecular biology of MITF suggests that the MITF pathway may provide molecular targets for certain bone disorders. ..

..The genetics and molecular biology of MITF suggests that the MITF pathway may provide molecular targets for certain bone disorders. ..

..PUBLIC HEALTH RELEVANCE: This application will study CLC channels, which are chloride channels critical for chloride ion transports across cell membranes...

..PUBLIC HEALTH RELEVANCE: This application will study CLC channels, which are chloride channels critical for chloride ion transports across cell membranes...

..The broad objective of our studies is to uncover leads that could translate into new treatments for cystic fibrosis. ..

..intestinal tissues to determine a role for membrane traffic in regulated CFTR and other potential alternate chloride channels and anion transport...

..The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS PageNumbers Face Page ' Description, ..

..The following studies will examine the role of these lipids in exacerbating the symptoms of Cystic fibrosis and will be used in developing new therapeutic approaches for this disease. ..

..The following studies will examine the role of these lipids in exacerbating the symptoms of Cystic fibrosis and will be used in developing new therapeutic approaches for this disease. ..

..This proposal seeks to understand the mechanisms that regulate CFTR movement into to the membrane under physiological conditions in the intestine in order to elucidate how dysfunction of CFTR leads to either CF or secretory diarrhea. ..

..This proposal seeks to understand the mechanisms that regulate CFTR movement into to the membrane under physiological conditions in the intestine in order to elucidate how dysfunction of CFTR leads to either CF or secretory diarrhea. ..

..Preliminary results of inhibitor and pH sensitivity suggest that the recorded single Cl- channels may participate in HC1 accumulation...