Chloride channel diseases resulting from impaired transepithelial transport or vesicular function

Jentsch, Thomas J.; Maritzen, Tanja; Zdebik, Anselm A.

doi:10.1172/jci25470

Cited by 121 publications

(78 citation statements)

References 101 publications

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“…However, the exact role of CFTR in regulating organelle pH remains controversial, with hyper-rather than hypo-acidification suggested to occur in CF respiratory epithelial cells (17). Recent findings about the endosomal protein ClC-5, which belongs to the CLC family of Cl Ϫ channels/exchangers, have provided insights into the role of anion transporters in PT cells (18). In normal conditions, low molecular weight (LMW) proteins as well as albumin and transferrin in some species are ultrafiltered by the glomerular membrane but almost entirely reabsorbed by receptor-mediated endocytosis at the apical side of PT cells (19).…”

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“…The loss of ClC-5, which co-distributes with the vacuolar H ϩ -ATPase (V-ATPase) in PT endosomes, causes a major defect in receptor-mediated endocytosis and an LMW proteinuria in Clcn5 knockout (KO) mice (20,21) as in patients with Dent's disease, which is caused by inactivating mutations in CLCN5 (22). By analogy, other intracellular anionic transporters such as CFTR might play a role in the endocytic reabsorption of LMW proteins by the kidney (4,18). In this study, we describe the segmental and subcellular distribution of CFTR in the kidney, at both the mRNA and protein levels.…”

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Cystic Fibrosis Is Associated with a Defect in Apical Receptor–Mediated Endocytosis in Mouse and Human Kidney

Jouret¹,

Bernard²,

Hermans³

et al. 2007

Journal of the American Society of Nephrology

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Inactivation of the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) causes cystic fibrosis (CF).Although CFTR is expressed in the kidney, no overwhelming renal phenotype has been documented in patients with CF. This study investigated the expression, subcellular distribution, and processing of CFTR in the kidney; used various mouse models to assess the role of CFTR in proximal tubule (PT) endocytosis; and tested the relevance of these findings in patients with CF. The level of CFTR mRNA in mouse kidney approached that found in lung. CFTR was located in the apical area of PT cells, with a maximal intensity in the straight part (S3) of the PT. Fractionation showed that CFTR co-distributed with the chloride/proton exchanger ClC-5 in PT endosomes. Cftr ؊/؊ mice showed impaired 125 I-␤ 2 -microglobulin uptake, together with a decreased amount of the multiligand receptor cubilin in the S3 segment and a significant loss of cubilin and its low molecular weight (LMW) ligands into the urine. Defective receptor-mediated endocytosis was found less consistently in Cftr ⌬F/⌬F mice, characterized by a large phenotypic heterogeneity and moderate versus mice that lacked ClC-5. A significant LMW proteinuria (and particularly transferrinuria) also was documented in a cohort of patients with CF but not in patients with asthma and chronic lung inflammation. In conclusion, CFTR inactivation leads to a moderate defect in receptor-mediated PT endocytosis, associated with a cubilin defect and a significant LMW proteinuria in mouse and human. The magnitude of the endocytosis defect that is caused by CFTR versus ClC-5 loss likely reflects functional heterogeneity along the PT.

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Cystic Fibrosis Is Associated with a Defect in Apical Receptor–Mediated Endocytosis in Mouse and Human Kidney

Jouret¹,

Bernard²,

Hermans³

et al. 2007

Journal of the American Society of Nephrology

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“…Apesar disso, esse processo de maturação conformacional de CFTR é considerado pouco eficiente, pois 75% das moléculas CFTR normais são degradadas pelo aparato de controle de qualidade logo após a sua síntese (17) . (18,21) .…”

Section: 34aspectos Celulares E Moleculares Dos Canais Cftr E Enacunclassified

Canais Iônicos E Fibrose Cística

Coutinho¹,

Figueiredo²,

Tintino³

et al. 2014

Rev. Interf. FLS

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_________________________________________________________________________________ RESUMOIntrodução: A Fibrose Cística (FC) é uma doença autossômica recessiva letal, que acomete preferencialmente crianças brancas. Objetivo: Descrever e discutir os mecanismos moleculares envolvidos na FC. Materiais e métodos: Artigos obtidos nos bancos de dados internacionais SCIELO, PUBMED, BIOLINE, DOAJ e HIGHWIRE que tratam dos mecanismos moleculares envolvidos na FC. Resultados e discussões: Decorre de mutações no gene que codifica a proteína "regulador de condutância transmembrana da fibrose cística" (CFTR). Esta contribui para a regulação do fluxo iônico nas superfícies apicais das células epiteliais, e é um canal de cloreto. A fisiopatologia da FC envolve o bloqueio da secreção do cloreto através da membrana apical das células epiteliais glandulares, resultando em seu acúmulo intracelular, acompanhado do influxo de sódio e água para este compartimento. Como consequência, ocorre desidratação da superfície celular com formação de secreções espessas -características da doença. O diagnóstico é baseado na clínica, demonstração laboratorial de concentrações elevadas de cloreto no suor e análise genética. O tratamento inclui: fluidificação das vias aéreas, antibioticoterapia, broncodilatadores, suporte nutricional e reposição enzimas. Na tentativa de aumentar o efluxo epitelial de Cl -ou inibir o influxo do Na + , alvos moleculares podem ser atacados por diferentes drogas como reguladores de migração citoplasmática, ativadores da expressão gênica, entre outros, para o primeiro, e inativação dos ENaC (amilorida ou benzamil) ou inibição do influxo de sódio (ouabaína, digoxina ou loperamida). Considerações Finais: Novas modalidades terapêuticas e a detecção precoce da FC por genotipagem podem melhorar o prognóstico e a qualidade de vida dos afetados. Palavras -chave:Fibrose Cística, Canalopatias, CFTR, EnaC, F508. ABSTRACTIntroduction: Cystic Fibrosis (CF) is a lethal autossomic recessive disease occurring mainly in white kids. Objective: Describe and discuss the molecular mechanisms involved in the CF. Material and methods: article obtained from the international databanks SCIELO, PUBMED, BIOLINE, DOAJ and HIGHWIRE about the molecular mechanisms of CF. Results and discussions: Its due mutations on the gene of cystic fibrosis Transmembrane conductance regulator (CFTR). This protein contributes for the regulation of the ionic flow in the apical surfaces of the epithelial cells, and is a chloride canal. The physiopathology of the CF involves the blockade of the chloride secretion through the apical membrane of the epithelial cells, resulting in intracellular accumulation, followed by the sodium and water influx. As consequence will occur a dehidratation of the cellular surface with thick secretion. The diagnosis is based on the clinic, the laboratorial identification of high concentrations of chloride in the sweat and genetic analysis. The treatment includes: rehidratation of the airway, antibiothicotherapy, nutritional support and en...

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“…13 For example, a defect in alanine, histidine, threonine, aspartic acid, and cysteine amino acids leads to mutation or change in CLCNKB a ion channel that causes type III of Bartter's syndrome. 16 Thus, the study of the structural and binding environments of inorganic atoms within these channels has important implications. The knowledge of the structure of these channels can be increased by studying the hydrogen bonds.…”

Section: Introductionmentioning

confidence: 99%

DFT studies of NH–Cl hydrogen bond of amino acid hydrochloride salts in ion channels

Moridi

Shekarsaraei

Hadipour

2016

ACSi

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Quantum chemical calculations were made, to study NH-Cl hydrogen bonds of two amino acid hydrochloride salts called alanine and threonine. The Nuclear Magnetic Resonance and Nuclear Quadrupole Resonance parameters for nitrogen and chlorine were calculated via four functionals such as, B3LYP, M062X, M06L, and CAM-B3LYP and by applying the 6-311++G(d,p) basis set. One of the functionals produced more accurate results. Geometry optimization was performed using the M062X/6-31++G(d,p) method, and Natural Bond Orbitals analysis was performed by applying the M062X/6-311++G(d,p) level. This study examined Nuclear Magnetic Resonance and Nuclear Quadrupole Resonance parameters with changes in structure from monomer to pentamer and investigated correlations between Natural Bond Orbitals parameters and Nuclear Magnetic Resonance or Nuclear Quadrupole Resonance parameters. The Natural Bond Orbitals parameters were used to investigate changes in structural parameters along with crystal development.

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Chloride channel diseases resulting from impaired transepithelial transport or vesicular function

Cited by 121 publications

References 101 publications

Cystic Fibrosis Is Associated with a Defect in Apical Receptor–Mediated Endocytosis in Mouse and Human Kidney

Cystic Fibrosis Is Associated with a Defect in Apical Receptor–Mediated Endocytosis in Mouse and Human Kidney

Canais Iônicos E Fibrose Cística

DFT studies of NH–Cl hydrogen bond of amino acid hydrochloride salts in ion channels

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