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      Cystic Fibrosis Transmembrane Conductance Regulator in the Kidney: Clues to Its Role?

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          The cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic adenosine monophosphate dependent, low-conductance chloride channel found on the apical plasma membrane of secretory epithelia. Surprisingly, since cystic fibrosis patients have no kidney phenotype, CFTR is highly expressed in the kidney, present from 12 weeks of gestation in the human metanephric kidney. As well as the mature, full-length, 165-kD wild-type protein (WT-CFTR) associated with renal tubule plasma membranes, intracellular, partially glycosylated forms are also seen in normal kidneys. In addition, a kidney-specific splice variant of CFTR translates a cytoplasmic truncated protein (TNR-CFTR), apparently associated with a specific small endosomal population, and is predominantly expressed in the renal medulla. WT-CFTR and TNR-CFTR show different patterns of developmental regulation, WT-CFTR being the major form expressed early in metanephric development when it is localized at the apical plasma membrane of developing collecting tubules. By contrast, TNR-CFTR expression increases with gestational age, reaching adult levels at 23 weeks. Evidence suggests that WT-CFTR plays a role in chloride secretion into the apical lumen of normal distal tubules. In autosomal dominant polycystic kidney disease, normally targeted CFTR at the apical plasma membrane in association with mislocalized Na-K-ATPase may result in abnormal fluid secretion into cysts. Similar colocalization of WT-CFTR and Na-K-ATPase at the apical plasma membranes is found in collecting tubules during development when it is speculated to play a role in the initiation of opening of the tubule lumen.

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          Most cited references 5

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          Mislocalization of delta F508 CFTR in cystic fibrosis sweat gland.

          Misprocessing and mislocalization of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) has been described for the major CF-causing mutation (delta F508) in heterologous expression systems in vitro. We have generated monoclonal antibodies (mAbs) to CFTR with the aim of localizing the protein and its CF variants in vivo. Of the tissues where CFTR was observed, only the sweat gland is readily available and does not undergo secondary changes due to CF disease pathology. Sweat ducts from CF patients homozygous for delta F508 did not show the typical apical membrane staining seen in control biopsies. This demonstrates that the biosynthetic arrest and intracellular retention of delta F508 CFTR initially observed in vitro does occur in vivo and emphasizes the need to focus efforts on understanding the mislocalization.
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            Cyclic AMP-dependent protein kinase opens chloride channels in normal but not cystic fibrosis airway epithelium.

            Chloride (Cl-) secretion by the airway epithelium regulates, in part, the quantity and composition of the respiratory tract fluid, thereby facilitating mucociliary clearance. The rate of Cl- secretion is controlled by apical membrane Cl- channels. Apical Cl- channels are opened and Cl- secretion is stimulated by a variety of hormones and neurotransmitters that increase intracellular levels of cyclic AMP (cAMP). In cystic fibrosis (CF), a common lethal genetic disease of Caucasians, airway, sweat-gland duct, secretory-coil and possibly other epithelia are anion impermeable. This abnormality may explain several of the clinical manifestations of the disease. The Cl- impermeability in CF-airway epithelia has been localized to the apical cell membrane, where regulation of Cl- channels is abnormal: hormonal secretagogues stimulate cAMP accumulation appropriately but Cl- channels fail to open. Here we report that the purified catalytic subunit of cAMP-dependent protein kinase plus ATP opens Cl- channels in excised, cell-free patches of membrane from normal cells, but fails to open Cl- channels in CF cells. These results indicate that in normal cells, the cAMP-dependent protein kinase phosphorylates the Cl- channel or an associated regulatory protein, causing the channel to open. The failure of CF Cl- channels to open suggests a defect either in the channel or in such an associated regulatory protein.
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              Cloning of cDNA for the glutamate-binding subunit of an NMDA receptor complex.

              The amino acids L-glutamic and L-aspartic acids form the most widespread excitatory transmitter network in mammalian brain. The excitation produced by L-glutamic acid is important in the early development of the nervous system, synaptic plasticity and memory formation, seizures and neuronal degeneration. The receptors activated by L-glutamic acid are a target for therapeutic intervention in neurodegenerative diseases, brain ischaemia and epilepsy. There are two types of receptors for the excitatory amino acids, those that lead to the opening of cation-selective channels and those that activate phospholipase C (ref. 11). The receptors activating ion channels are NMDA (N-methyl-D-aspartate) and kainate/AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate)-sensitive receptors. The complementary DNAs for the kainate/AMPA receptor and for the metabotropic receptor have been cloned. We report here on the isolation and characterization of a protein complex of four major proteins that represents an intact complex of the NMDA receptor ion channel and on the cloning of the cDNA for one of the subunits of this receptor complex, the glutamate-binding protein.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                August 1999
                26 July 1999
                : 7
                : 4
                : 284-289
                Mount Sinai School of Medicine, New York, N.Y., USA
                20615 Exp Nephrol 1999;7:284–289
                © 1999 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 1, References: 43, Pages: 6
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