Structure, Gating, and Regulation of the CFTR Anion Channel

Csanády, László; Vergani, Paola; Gadsby, David C.

doi:10.1152/physrev.00007.2018

Cited by 192 publications

(188 citation statements)

References 283 publications

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“…CF is the most common autosomal recessive disorder affecting Caucasians [4], currently affecting >30,000 patients in the US and >70,000 patients worldwide [4,5] with approximately 1000 new cases diagnosed each year [5,6]. The CFTR gene encodes a cAMP-regulated anion channel [7,8] and mutations in the CFTR gene lead to ion imbalance and dysregulation of fluid secretions within a variety of organs including lung, GI and reproductive tracts, pancreas, and skin [6,9].…”

Section: Introductionmentioning

confidence: 99%

CFTR dysregulation drives active selection of the gut microbiome

et al. 2020

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Patients with cystic fibrosis (CF) have altered fecal microbiomes compared to those of healthy controls. The magnitude of this dysbiosis correlates with measures of CF gastrointestinal (GI) disease, including GI inflammation and nutrient malabsorption. However, whether this dysbiosis is caused by mutations in the CFTR gene, the underlying defect in CF, or whether CF-associated dysbiosis augments GI disease was not clear. To test the relationships between CFTR dysfunction, microbes, and intestinal health, we established a germ-free (GF) CF mouse model and demonstrated that CFTR gene mutations are sufficient to alter the GI microbiome. Furthermore, flow cytometric analysis demonstrated that colonized CF mice have increased mesenteric lymph node and spleen TH17+ cells compared with non-CF mice, suggesting that CFTR defects alter adaptive immune responses. Our findings demonstrate that CFTR mutations modulate both the host adaptive immune response and the intestinal microbiome.

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Section: Introductionmentioning

confidence: 99%

CFTR dysregulation drives active selection of the gut microbiome

et al. 2020

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“…CFTR (ABCC7) is the member of the ATP binding cassette (ABC) superfamily. It consists of two transmembrane domains (TMD1 and TMD2), each consisting of 6 TM helices, two nucleotide binding domains (NBD1 and NBD2), and a disordered segment, called regulatory (R) domain [4,5]. The R domain phosphorylation is a prerequisite for channel gating.…”

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confidence: 99%

Discovering the chloride pathway in the CFTR channel

Farkas

Tordai

Padányi

et al. 2019

Cell. Mol. Life Sci.

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Cystic fibrosis (CF), a lethal monogenic disease, is caused by pathogenic variants of the CFTR chloride channel. The majority of CF mutations affect protein folding and stability leading overall to diminished apical anion conductance of epithelial cells. The recently published cryo-EM structures of full-length human and zebrafish CFTR provide a good model to gain insight into structure-function relationships of CFTR variants. Although, some of the structures were determined in the phosphorylated and ATP-bound active state, none of the static structures showed an open pathway for chloride permeation. Therefore, we performed molecular dynamics simulations to generate a conformational ensemble of the protein and used channel detecting algorithms to identify conformations with an opened channel. Our simulations indicate a main intracellular entry at TM4/6, a secondary pore at TM10/12, and a bottleneck region involving numerous amino acids from TM1, TM6, and TM12 in accordance with experiments. Since chloride ions entered the pathway in our equilibrium simulations, but did not traverse the bottleneck region, we performed metadynamics simulations, which revealed two possible exits. One of the chloride ions exits includes hydrophobic lipid tails that may explain the lipid-dependency of CFTR function. In summary, our in silico study provides a detailed description of a potential chloride channel pathway based on a recent cryo-EM structure and may help to understand the gating of the CFTR chloride channel, thus contributing to novel strategies to rescue dysfunctional mutants.

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“…Hence, our observation that PT disturbs ASL homeostasis might reflect an impact on vectorial ion transport, either activating apical chloride channels or inhibiting ENaC. It has been demonstrated that PT intoxication results in increased intracellular cAMP levels, and CFTR is activated by intracellular cAMP 61 . Yet, future studies, including Ussing chamber measurements, will be required to decipher the impact of PT intoxication on transepithelial ion/water transport in more detail.…”

Section: Discussionmentioning

confidence: 83%

Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo

Ernst

Mittler

Winkelmann

et al. 2020

Preprint

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Whooping cough is caused by Bordetella pertussis that releases pertussis toxin (PT) which comprises enzyme A-subunit PTS1 and binding/transport B-subunit. After receptor-mediated endocytosis, PT reaches the endoplasmic reticulum from where unfolded PTS1 is transported to the cytosol. PTS1 ADP-ribosylates G-protein α-subunits resulting in increased cAMP signaling. Here, the role of target cell chaperones Hsp90, Hsp70, cyclophilins and FK506-binding proteins for cytosolic PTS1-uptake is characterized in detail. PTS1 specifically and directly interacts with chaperones in vitro and in cells. Specific pharmacological chaperone inhibition protects CHO-K1, human primary airway basal cells and a fully differentiated airway epithelium from PT-intoxication by reducing cytosolic PTS1-amounts without affecting cell binding or enzyme activity. PT is internalized by human airway epithelium secretory but not ciliated cells and leads to increase of apical surface liquid. Cyclophilin-inhibitors reduced leukocytosis in infant mouse model of pertussis, indicating their promising potential for developing novel therapeutic strategies against whooping cough.

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Structure, Gating, and Regulation of the CFTR Anion Channel

Cited by 192 publications

References 283 publications

CFTR dysregulation drives active selection of the gut microbiome

CFTR dysregulation drives active selection of the gut microbiome

Discovering the chloride pathway in the CFTR channel

Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo

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