Modulation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Activity and Genistein Binding by Cytosolic pH

Melani, Raffaella; Tomati, Valeria; Galietta, Luis J. V.; Zegarra‐Moran, Olga

doi:10.1074/jbc.m110.166850

Cited by 12 publications

(10 citation statements)

References 36 publications

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“…The efficacy (maximum quenching rate) of the iodide influx driven by the anionophore EH160 is similar to the CFTR activated by applying 20 μM forskolin and 10 μM genistein in FRT cells (Hernando et al, 2018 ). Since the CFTR activity of the CFTR transfected in the FRT cells is more than 13-fold greater that expected in human bronchial cells (Taddei et al, 2004 ; Moran et al, 2005 ; Kreindler et al, 2009 ; Melani et al, 2010 ; Gianotti et al, 2013 , 2016 ). Thus, to induce an anion transport equivalent to that expected in bronchial cells, it would be necessary to apply <0.5 μM of EH160, significantly increasing the width of the therapeutic window.…”

Section: Discussionmentioning

confidence: 93%

Anion-Transport Mechanism of a Triazole-Bearing Derivative of Prodigiosine: A Candidate for Cystic Fibrosis Therapy

et al. 2018

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Cystic fibrosis (CF) is a genetic lethal disease, originated from the defective function of the CFTR protein, a chloride and bicarbonate permeable transmembrane channel. CF mutations affect CFTR protein through a variety of molecular mechanisms which result in different functional defects. Current therapeutic approaches are targeted to specific groups of patients that share a common functional defect. We seek to develop an innovative therapeutic approach for the treatment of CF using anionophores, small molecules that facilitate the transmembrane transport of anions. We have characterized the anion transport mechanism of a synthetic molecule based on the structure of prodigiosine, a red pigment produced by bacteria. Anionophore-driven chloride efflux from large unilamellar vesicles is consistent with activity of an uniporter carrier that facilitates the transport of anions through lipid membranes down the electrochemical gradient. There are no evidences of transport coupling with protons. The selectivity sequence of the prodigiosin inspired EH160 ionophore is formate > acetate > nitrate > chloride > bicarbonate. Sulfate, phosphate, aspartate, isothionate, and gluconate are not significantly transported by these anionophores. Protonation at acidic pH is important for the transport capacity of the anionophore. This prodigiosin derived ionophore induces anion transport in living cells. Its low toxicity and capacity to transport chloride and bicarbonate, when applied at low concentration, constitute a promising starting point for the development of drug candidates for CF therapy.

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Section: Discussionmentioning

confidence: 93%

Anion-Transport Mechanism of a Triazole-Bearing Derivative of Prodigiosine: A Candidate for Cystic Fibrosis Therapy

et al. 2018

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“…; Melani et al . ), the 10% CO 2 ‐induced acidosis of ∼0.2 units is unlikely to significantly alter CFTR activity based on single channel recordings of CFTR expressed in mammalian cells (Chen et al . ) and measurements of CFTR‐dependent Cl − conductance made in human sweat ducts (Reddy et al .…”

Section: Discussionmentioning

confidence: 99%

Hypercapnia modulates cAMP signalling and cystic fibrosis transmembrane conductance regulator‐dependent anion and fluid secretion in airway epithelia

Turner

Saint‐Criq

Patel

et al. 2015

The Journal of Physiology

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Key points Raised arterial blood CO2 (hypercapnia) is a feature of many lung diseases.CO2 has been shown to act as a cell signalling molecule in human cells, notably by influencing the levels of cell signalling second messengers: cAMP and Ca2+.Hypercapnia reduced cAMP‐stimulated cystic fibrosis transmembrane conductance regulator‐dependent anion and fluid transport in Calu‐3 cells and primary human airway epithelia but did not affect cAMP‐regulated HCO3 − transport via pendrin or Na+/HCO3 − cotransporters.These results further support the role of CO2 as a cell signalling molecule and suggests CO2‐induced reductions in airway anion and fluid transport may impair innate defence mechanisms of the lungs. AbstractHypercapnia is clinically defined as an arterial blood partial pressure of CO2 of above 40 mmHg and is a feature of chronic lung disease. In previous studies we have demonstrated that hypercapnia modulates agonist‐stimulated cAMP levels through effects on transmembrane adenylyl cyclase activity. In the airways, cAMP is known to regulate cystic fibrosis transmembrane conductance regulator (CFTR)‐mediated anion and fluid secretion, which contributes to airway surface liquid homeostasis. The aim of the current work was to investigate if hypercapnia could modulate cAMP‐regulated ion and fluid transport in human airway epithelial cells. We found that acute exposure to hypercapnia significantly reduced forskolin‐stimulated elevations in intracellular cAMP as well as both adenosine‐ and forskolin‐stimulated increases in CFTR‐dependent transepithelial short‐circuit current, in polarised cultures of Calu‐3 human airway cells. This CO2‐induced reduction in anion secretion was not due to a decrease in HCO3 − transport given that neither a change in CFTR‐dependent HCO3 − efflux nor Na+/HCO3 − cotransporter‐dependent HCO3 − influx were CO2‐sensitive. Hypercapnia also reduced the volume of forskolin‐stimulated fluid secretion over 24 h, yet had no effect on the HCO3 − content of the secreted fluid. Our data reveal that hypercapnia reduces CFTR‐dependent, electrogenic Cl− and fluid secretion, but not CFTR‐dependent HCO3 − secretion, which highlights a differential sensitivity of Cl− and HCO3 − transporters to raised CO2 in Calu‐3 cells. Hypercapnia also reduced forskolin‐stimulated CFTR‐dependent anion secretion in primary human airway epithelia. Based on current models of airways biology, a reduction in fluid secretion, associated with hypercapnia, would be predicted to have important consequences for airways hydration and the innate defence mechanisms of the lungs.

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“…Importantly, genistein interacts with another member of the ABC transporter family, Cystic Fibrosis Transmembrane Regulator (CFTR; ABCC7), to potentiate function at low concentrations and inhibit CFTR at higher concentrations. 37 The possibility exists, therefore, that genistein interacts with Pgp in a similar concentration-dependent manner and this is the cause of the mixed results observed. Finally, with respect to our findings at 100 lM genistein in the Caco-2 vectorial transport model, this same concentration has been shown to reduce cimetidine B to A transport in Caco-2 cells.…”

Section: Discussionmentioning

confidence: 99%

Glyceollin Transport, Metabolism, and Effects on P-Glycoprotein Function in Caco-2 Cells

Chimezie

Quadri

Cole

et al. 2014

Journal of Medicinal Food

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Glyceollins are phytoalexins produced in soybeans from their isoflavone precursor daidzein. Their impressive anticancer and glucose normalization effects in rodents have generated interest in their therapeutic potential. The aim of the present studies was to begin to understand glyceollin intestinal transport and metabolism, and their potential effects on P-glycoprotein (Pgp) in Caco-2 cells. At 10 and 25 μM, glyceollin permeability was 2.4±0.16×10(-4) cm/sec and 2.1±0.15×10(-4) cm/sec, respectively, in the absorptive direction. Basolateral to apical permeability at 25 μM was 1.6±0.10×10(-4) cm/sec. Results suggest high absorption potential of glyceollin by a passive-diffusion-dominated mechanism. A sulfate conjugate at the phenolic hydroxyl position was observed following exposure to Caco-2 cells. In contrast to verapamil inhibition of the net secretory permeability of rhodamine 123 (R123) and its enhancement of calcein AM uptake into Caco-2 cells, neither glyceollin nor genistein inhibited Pgp (MDR1; ABCB1) up to 300 μM. There was no significant change in MDR1 mRNA expression, Pgp protein expression, or R123 transport in cells exposed to glyceollin or genistein for 24 h up to 100 μM. Collectively, these results suggest that glyceollin has the potential to be well absorbed, but that, similar to the isoflavone genistein, its absorption may be reduced substantially by intestinal metabolism; further, they indicate that glyceollin does not appear to alter Pgp function in Caco-2 cells.

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Modulation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Activity and Genistein Binding by Cytosolic pH

Cited by 12 publications

References 36 publications

Anion-Transport Mechanism of a Triazole-Bearing Derivative of Prodigiosine: A Candidate for Cystic Fibrosis Therapy

Anion-Transport Mechanism of a Triazole-Bearing Derivative of Prodigiosine: A Candidate for Cystic Fibrosis Therapy

Hypercapnia modulates cAMP signalling and cystic fibrosis transmembrane conductance regulator‐dependent anion and fluid secretion in airway epithelia

Glyceollin Transport, Metabolism, and Effects on P-Glycoprotein Function in Caco-2 Cells

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