Physiology of Epithelial Chloride and Fluid Secretion

Frizzell, Raymond A.; Hanrahan, John W.

doi:10.1101/cshperspect.a009563

Cited by 205 publications

(216 citation statements)

References 136 publications

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“…While the relevance of fluid movement in increasing the size of the cavity has been demonstrated in several experimental models 5,10,11 , with the involvement of paracellular transportation and epithelial chloride secretion 9,23 , its role in shaping the lumen has still not been evaluated. It is widely assumed that the increased intraluminal concentration of chloride (and other ions) promotes the movement of water from outside the organ into the lumen (by paracellular or transcellular transport), similar to what occurs in secretory epithelial organs 12,13 . Thus, this transepithelial transportation is thought to be what drives lumen growth.…”

Section: Articlementioning

confidence: 96%

“…Fluids ingress has been shown to rely on a functional Na þ /K þ ATPase pump, the CFTR chloride channel and the formation of both paracellular pores and barriers by claudin proteins 5,[9][10][11] . The present view of the process indicates that fluid ingress is mediated by transepithelial fluid transport, in which the epithelium is considered as a pump driving fluid movement from outside of the organ into the lumen [12][13][14] . Remarkably, although this epithelium is also a fluid-filled structure, the exact contribution of intraepithelial fluid to lumen morphogenesis is unclear.…”

mentioning

confidence: 97%

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Mitotic cell rounding and epithelial thinning regulate lumen growth and shape

et al. 2015

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Many organ functions rely on epithelial cavities with particular shapes. Morphogenetic anomalies in these cavities lead to kidney, brain or inner ear diseases. Despite their relevance, the mechanisms regulating lumen dimensions are poorly understood. Here, we perform live imaging of zebrafish inner ear development and quantitatively analyse the dynamics of lumen growth in 3D. Using genetic, chemical and mechanical interferences, we identify two new morphogenetic mechanisms underlying anisotropic lumen growth. The first mechanism involves thinning of the epithelium as the cells change their shape and lose fluids in concert with expansion of the cavity, suggesting an intra-organ fluid redistribution process. In the second mechanism, revealed by laser microsurgery experiments, mitotic rounding cells apicobasally contract the epithelium and mechanically contribute to expansion of the lumen. Since these mechanisms are axis specific, they not only regulate lumen growth but also the shape of the cavity.

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Section: Articlementioning

confidence: 96%

mentioning

confidence: 97%

Mitotic cell rounding and epithelial thinning regulate lumen growth and shape

et al. 2015

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“…Backbone RMSD (Å) differences between reported CFTR models. Models [1, 2, 3 and 12], [4][5][6] and [13][14], [7][8][9], [10][11] and [15][16] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 …”

Section: Discussionmentioning

confidence: 99%

“…This layer is readily colonized by bacteria ultimately resulting in chronic disease and lung failure. 2,4 Human CFTR is a 1,480-residue glycoprotein, which belongs to the ABC (ATP-Binding Cassette) transporter superfamily. [5][6] Yet, in contrast with other members of this group, CFTR is the only ABC transporter known to function as an ion channel.…”

Section: Introduction Cystic Fibrosis (Cf) Is a Lethal Inherited Dismentioning

confidence: 99%

Molecular Dynamics Flexible Fitting Simulations Identify New Models of the Closed State of the Cystic Fibrosis Transmembrane Conductance Regulator Protein

Simhaev

McCarty

Ford

et al. 2017

J. Chem. Inf. Model.

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Cystic Fibrosis (CF) is a lethal, genetic disease found in particular in humans of European origin which is caused by mutations in the CFTR chloride channel. The search for CF therapies acting by modulating the impaired function of mutant CFTR will be greatly advanced by high resolution structures of CFTR in different states. To date, two medium resolution EM structures of CFTR are available (one of a distant zebrafish (Danio rerio) CFTR ortholog and one of human CFTR). The two models are nearly identical to one another and both correspond to the inward-facing, NBDs separated, closed state of the channel. In addition, lower resolution structural data are available for human CFTR in an alternative conformation which likely features associated NBDs and thus geometrically resembles the conducting state of the channel.Multiple homology models of human CFTR in multiple states have been developed over the years, yet their correspondence to the existing structural information is unexplored. In this work we use molecular dynamics flexible fitting (MDFF) simulations to refine two previously described CFTR models based on the available cryo-EM map of the human protein. This map was recorded in the absence of ATP and consequently represents closed-state CFTR yet its features likely correspond to a NBDs associated conformation of the protein. Accordingly, the resulting models feature dimerized NBDs yet with no membrane traversing pore. Moreover, the open probability of the new models as deduced from the MDFF trajectories is significantly lower than that deduced from control MD trajectories initiated from the starting models. We propose that the new models correspond to a CFTR conformation which to date was largely unexplored yet one that is relevant to the gating cycle of the protein. In particular this conformation may participate in rapid channel opening and closing through small allosteric movements controlled by nucleotide binding and dissociation events. Analyzing the resulting trajectories (and not only the final models as is usually the case), we demonstrate that the refined models have good stereochemical properties and are also in favorable agreement with multiple experimental data.Moreover, despite different starting points, the final models share many common features.Finally, we propose that the combination of high resolution cryo-EM maps which are currently emerging from multiple labs and MDFF simulations will be of value for the development of yet more reliable CFTR models as well as for the identification of binding sites for CFTR modulators.

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“…Cl − entry into the cell occurs primarily through the basolateral Na + /K + /2Cl − cotransporter (NKCC) (51). After CFTR reaches >50% of WT levels, Cl − secretion plateaus as Cl − entry into the cell becomes rate-limiting.…”

Section: Increasing Cftr Expression Progressively Enhances Asl Host Dmentioning

confidence: 99%

Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

Shah

Ernst

Tang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. Airway disease is the major source of morbidity and mortality. Successful implementation of gene- and cell-based therapies for CF airway disease requires knowledge of relationships among percentages of targeted cells, levels of CFTR expression, correction of electrolyte transport, and rescue of host defense defects. Previous studies suggested that, when ∼10–50% of airway epithelial cells expressed CFTR, they generated nearly wild-type levels of Cl− secretion; overexpressing CFTR offered no advantage compared with endogenous expression levels. However, recent discoveries focused attention on CFTR-mediated HCO3− secretion and airway surface liquid (ASL) pH as critical for host defense and CF pathogenesis. Therefore, we generated porcine airway epithelia with varying ratios of CF and wild-type cells. Epithelia with a 50:50 mix secreted HCO3− at half the rate of wild-type epithelia. Likewise, heterozygous epithelia (CFTR+/− or CFTR+/∆F508) expressed CFTR and secreted HCO3− at ∼50% of wild-type values. ASL pH, antimicrobial activity, and viscosity showed similar relationships to the amount of CFTR. Overexpressing CFTR increased HCO3− secretion to rates greater than wild type, but ASL pH did not exceed wild-type values. Thus, in contrast to Cl− secretion, the amount of CFTR is rate-limiting for HCO3− secretion and for correcting host defense abnormalities. In addition, overexpressing CFTR might produce a greater benefit than expressing CFTR at wild-type levels when targeting small fractions of cells. These findings may also explain the risk of airway disease in CF carriers.

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Physiology of Epithelial Chloride and Fluid Secretion

Cited by 205 publications

References 136 publications

Mitotic cell rounding and epithelial thinning regulate lumen growth and shape

Mitotic cell rounding and epithelial thinning regulate lumen growth and shape

Molecular Dynamics Flexible Fitting Simulations Identify New Models of the Closed State of the Cystic Fibrosis Transmembrane Conductance Regulator Protein

Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

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Physiology of Epithelial Chloride and Fluid Secretion

Cited by 205 publications

References 136 publications

Mitotic cell rounding and epithelial thinning regulate lumen growth and shape

Mitotic cell rounding and epithelial thinning regulate lumen growth and shape

Molecular Dynamics Flexible Fitting Simulations Identify New Models of the Closed State of the Cystic Fibrosis Transmembrane Conductance Regulator Protein

Relationships among CFTR expression, HCO 3 − secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

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Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies