Pharmacological treatment of the biochemical defect in cystic fibrosis airways

Rodgers, Helen; Knox, Alan J.

doi:10.1183/09031936.01.00086201

Cited by 20 publications

(12 citation statements)

References 63 publications

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“…4 Defective protein trafficking is thought to result from improper protein folding and/or incorrect molecule assembly and is associated with a growing number of human diseases. 5,6 With the recognition that some trafficking-defective membrane proteins are functional when induced to insert into the plasma membrane, the correction of protein trafficking abnormalities has been a therapeutic goal in a number of diseases, such as cystic fibrosis 7 and nephrogenic diabetes insipidus. 8 In LQT2, we previously reported that the HERG N470D mutation is trafficking defective when studied at a physiological temperature.…”

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confidence: 99%

Pharmacological Rescue of Human K ⁺ Channel Long-QT2 Mutations

et al. 2002

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Background-Defective protein trafficking is a consequence of gene mutations. Human long-QT (LQT) syndrome results from mutations in several genes, including the human ether-a-go-go-related gene (HERG), which encodes a delayed rectifier K ϩ current. Trafficking-defective mutant HERG protein is a mechanism for reduced delayed rectifier K ϩ current in LQT2, and high-affinity HERG channel-blocking drugs can result in pharmacological rescue. Methods and Results-We postulated that drug molecules modified to remove high-affinity HERG block may still stabilize mutant proteins in a conformation required for rescue. We tested terfenadine carboxylate (fexofenadine) and terfenadine, structurally similar drugs with markedly different affinities for HERG block, for rescue of traffickingdefective LQT2 mutations. Terfenadine rescued the N470D mutation but blocked the channels. In contrast, fexofenadine rescued N470D with a half-maximal rescue concentration of 177 nmol/L, which is Ϸ350-fold lower than the half-maximal channel block concentration. The G601S mutation was also rescued without channel block. Conclusions-Pharmacological rescue can occur without channel block. This could represent a new antiarrhythmic paradigm in the treatment of some trafficking-defective LQT2 mutations.

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Pharmacological Rescue of Human K ⁺ Channel Long-QT2 Mutations

et al. 2002

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“…Na via de fosforilação por PKA, essa proteína é ativada pelo aumento da concentração de AMPc via ciclase de adenilil (AC). Uma vez fosforilada, CFTR torna-se ativa e possibilita o efluxo de Cl -através da membrana apical da célula (20) .…”

Section: O Gene Da Fibrose Cística E Cftrunclassified

“…Como a proteína CFTR sofre a influência de diversos fatores para seu funcionamento normal que afetam a sua migração RE -Golgi -membrana plasmática -endossomo, sua expressão gênica e a sua ativação por fosforilação, existem diversos possíveis alvos moleculares para testar novas drogas no controle da ausência de efluxo de Cl -em pacientes com FC e CFTR -ΔF508 (20) . Dentre estes fatores estão: reguladores da migração citoplasmática, ativadores da expressão gênica, moduladores da fosforilação e inibidores de "stop codons".…”

Section: 381tratamento Farmacológico Para Cftrunclassified

“…Um tratamento complementar para a FC é evitar a absorção de Na+ através dos ENaC e da Na + -K + -ATPase, que são ativados por CFTR -ΔF508 (20,78) . Uma das tentativas de evitar a absorção de sódio através da membrana apical das células epiteliais consiste em inativar os ENaC.…”

Section: Tratamento Farmacológico Para Enacunclassified

“…O risco de um irmão do afetado (no caso, um novo filho do casal) ser homozigoto recessivo é de 25%, e de ser portador assintomático é de 50% (29) . (17,20) .…”

Section: Prognóstico E Aconselhamento Genéticounclassified

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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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Mutations in CNGA3 impair trafficking or function of cone cyclic nucleotide-gated channels, resulting in achromatopsia

et al. 2008

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CNGA3 encodes the A-subunit of the cone photoreceptor cyclic nucleotide-gated (CNG) channel, which is a crucial component of the phototransduction cascade in cone outer segments. Mutations in the CNGA3 gene have been associated with complete and incomplete forms of achromatopsia (ACHR), a congenital, autosomal recessively inherited retinal disorder characterized by lack of color discrimination, reduced visual acuity, nystagmus, and photophobia. Here we report the identification of three novel CNGA3 missense mutations in ACHR patients: c.682G>A (p.E228 K), c.1315C>T (p.R439W), and c.1405G>A (p.A469 T), and the detailed functional analyses of these new as well as five previously reported mutations (R283Q, T291R, F547L, G557R, and E590 K), in conjunction with clinical data of patients carrying these mutations, to establish genotype-phenotype correlations. The functional characterization of mutant CNGA3 channels was performed with calcium imaging and patch clamp recordings in a heterologous HEK293 cell expression system. Results were corroborated by immunostaining and colocalization experiments of the channel protein with the plasma membrane. Several mutations evoked pronounced alterations of the apparent cGMP sensitivity of mutant channels. These functional defects were fully or partially compensated by coexpressing the mutant CNGA3 subunit with the wild-type CNGB3 subunit for channels with the mutations R439W, A469 T, F547L, and E590 K. We could show that several mutant channels with agonist dose-response relationships similar to the wild-type exhibited severely impaired membrane targeting. In addition, this study presents the positive effect of reduced cell culture temperature on surface expression and functional performance of mutant CNG channels with protein folding or trafficking defects.

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Pharmacological treatment of the biochemical defect in cystic fibrosis airways

Cited by 20 publications

References 63 publications

Pharmacological Rescue of Human K ⁺ Channel Long-QT2 Mutations

Pharmacological Rescue of Human K ⁺ Channel Long-QT2 Mutations

Canais Iônicos E Fibrose Cística

Mutations in CNGA3 impair trafficking or function of cone cyclic nucleotide-gated channels, resulting in achromatopsia

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Pharmacological treatment of the biochemical defect in cystic fibrosis airways

Cited by 20 publications

References 63 publications

Pharmacological Rescue of Human K + Channel Long-QT2 Mutations

Pharmacological Rescue of Human K + Channel Long-QT2 Mutations

Canais Iônicos E Fibrose Cística

Mutations in CNGA3 impair trafficking or function of cone cyclic nucleotide-gated channels, resulting in achromatopsia

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Pharmacological Rescue of Human K ⁺ Channel Long-QT2 Mutations

Pharmacological Rescue of Human K ⁺ Channel Long-QT2 Mutations