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  • 1
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    Online Resource
    Exploitation of KESTREL to identify NDRG family members as physiological substrates for SGK1 and GSK3
    Portland Press Ltd. ; 2004
    In:  Biochemical Journal Vol. 384, No. 3 ( 2004-12-15), p. 477-488
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 384, No. 3 ( 2004-12-15), p. 477-488
    Abstract: We detected a protein in rabbit skeletal muscle extracts that was phosphorylated rapidly by SGK1 (serum- and glucocorticoid-induced kinase 1), but not by protein kinase Bα, and identified it as NDRG2 (N-myc downstream-regulated gene 2). SGK1 phosphorylated NDRG2 at Thr330, Ser332 and Thr348in vitro. All three residues were phosphorylated in skeletal muscle from wild-type mice, but not from mice that do not express SGK1. SGK1 also phosphorylated the related NDRG1 isoform at Thr328, Ser330 and Thr346 (equivalent to Thr330, Ser332 and Thr348 of NDRG2), as well as Thr356 and Thr366. Residues Thr346, Thr356 and Thr366 are located within identical decapeptide sequences GTRSRSHTSE, repeated three times in NDRG1. These threonines were phosphorylated in NDRG1 in the liver, lung, spleen and skeletal muscle of wild-type mice, but not in SGK1−/− mice. Knock-down of SGK1 in HeLa cells using small interfering RNA also suppressed phosphorylation of the threonine residues in the repeat region of NDRG1. The phosphorylation of NDRG1 by SGK1 transformed it into an excellent substrate for GSK3 (glycogen synthase kinase 3), which could then phosphorylate Ser342, Ser352 and Ser362 in the repeat region. Incubation of HeLa cells with the specific GSK3 inhibitor CT 99021 increased the electrophoretic mobility of NDRG1 in HeLa cells, demonstrating that this protein is phosphorylated by GSK3 in cells. Our results identify NDRG1 and NDRG2 as physiological substrates for SGK1, and demonstrate that phosphorylation of NDRG1 by SGK1 primes it for phosphorylation by GSK3.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20041057
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2004
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 2
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    Adenylyl cyclase 6 in acid-base balance – adding complexity
    Portland Press Ltd. ; 2018
    In:  Clinical Science Vol. 132, No. 17 ( 2018-09-14), p. 1995-1997
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 132, No. 17 ( 2018-09-14), p. 1995-1997
    Abstract: Systemic acid-base balance is tightly controlled within a narrow range of pH. Disturbances in systemic acid-base homeostasis are associated with diverse detrimental effects. The kidney is a key regulator of acid-base balance, capable of excreting HCO3− or H+, and chronic kidney disease invariably leads to acidosis. However, the regulatory pathways underlying the fine-tuned acid-base sensing and regulatory mechanisms are still incompletely understood. In the article published recently in Clinical Science (vol 132 (16) 1779-1796), Poulson and colleagues investigated the role of adenylyl cyclase 6 (AC6) in acid-base homeostasis. They uncovered a complex role of AC6, specifically affecting acid-base balance during HCO3− load, which causes pronounced alkalosis in AC6-deficient mice. However, the phenotype of AC6-deficient mice appears much more complex, involving systemic effects associated with increased energy expenditure. These observations remind us that there is much to be learned about the intricate signaling pathways involved in renal control of acid-base balance and the complex ramifications of acid-base regulation.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    URL: Article
    DOI: 10.1042/CS20180572
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2018
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  • 3
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    Control of liver cell function by the hydration state
    Portland Press Ltd. ; 1994
    In:  Biochemical Society Transactions Vol. 22, No. 2 ( 1994-05-01), p. 497-502
    Details
    In: Biochemical Society Transactions, Portland Press Ltd., Vol. 22, No. 2 ( 1994-05-01), p. 497-502
    Type of Medium: Online Resource
    ISSN: 0300-5127 , 1470-8752
    URL: Article
    DOI: 10.1042/bst0220497
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 1994
    SSG: 12
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  • 4
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    The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells
    Portland Press Ltd. ; 2000
    In:  Biochemical Journal Vol. 350, No. 1 ( 2000-08-15), p. 219-227
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 350, No. 1 ( 2000-08-15), p. 219-227
    Abstract: Transport of lactate and other monocarboxylates in mammalian cells is mediated by a family of transporters, designated monocarboxylate transporters (MCTs). The MCT4 member of this family has recently been identified as the major isoform of white muscle cells, mediating lactate efflux out of glycolytically active myocytes [Wilson, Jackson, Heddle, Price, Pilegaard, Juel, Bonen, Montgomery, Hutter and Halestrap (1998) J. Biol. Chem. 273, 15920–15926]. To analyse the functional properties of this transporter, rat MCT4 was expressed in Xenopus laevis oocytes and transport activity was monitored by flux measurements with radioactive tracers and by changes of the cytosolic pH using pH-sensitive microelectrodes. Similar to other members of this family, monocarboxylate transport via MCT4 is accompanied by the transport of H+ across the plasma membrane. Uptake of lactate strongly increased with decreasing extracellular pH, which resulted from a concomitant drop in the Km value. MCT4 could be distinguished from the other isoforms mainly in two respects. First, MCT4 is a low-affinity MCT: for l-lactate Km values of 17±3mM (pH-electrode) and 34±5mM (flux measurements with l-[U-14C] lactate) were determined. Secondly, lactate is the preferred substrate of MCT4. Km values of other monocarboxylates were either similar to the Km value for lactate (pyruvate, 2-oxoisohexanoate, 2-oxoisopentanoate, acetoacetate) or displayed much lower affinity for the transporter (β-hydroxybutyrate and short-chain fatty acids). Under physiological conditions, rat MCT will therefore preferentially transport lactate. Monocarboxylate transport via MCT4 could be competitively inhibited by α-cyano-4-hydroxycinnamate, phloretin and partly by 4,4´-di-isothiocyanostilbene-2,2´-disulphonic acid. Similar to MCT1, monocarboxylate transport via MCT4 was sensitive to inhibition by the thiol reagent p-chloromercuribenzoesulphonic acid.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/bj3500219
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2000
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells
    Portland Press Ltd. ; 2000
    In:  Biochemical Journal Vol. 350, No. 1 ( 2000-8-15), p. 219-
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 350, No. 1 ( 2000-8-15), p. 219-
    Type of Medium: Online Resource
    ISSN: 0264-6021
    URL: Article
    DOI: 10.1042/0264-6021:3500219
    RVK:
    WA 15000
    Language: Unknown
    Publisher: Portland Press Ltd.
    Publication Date: 2000
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 6
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    Association of 4F2hc with light chains LAT1, LAT2 or y+LAT2 requires different domains
    Portland Press Ltd. ; 2001
    In:  Biochemical Journal Vol. 355, No. 3 ( 2001-05-01), p. 725-731
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 355, No. 3 ( 2001-05-01), p. 725-731
    Abstract: Heterodimeric amino acid transporters are comprised of a type-II membrane protein named the heavy chain (4F2hc or rBAT) that may associate with a number of different polytopic membrane proteins, called light chains. It is thought that the heavy chain is mainly involved in the trafficking of the complex to the plasma membrane, whereas the transport process itself is catalysed by the light chain. The 4F2heavy chain (4F2hc) associates with at least six different light chains to induce distinct amino acid-transport activites. To test if the light chains are specifically recognized and to identify domains involved in the recognition of light chains, C-terminally truncated mutants of 4F2hc were constructed and co-expressed with the light chains LAT1, LAT2 and y+LAT2. The truncated isoform T1, comprised of only 133 amino acids that form the cytosolic N-terminus and the transmembrane helix, displayed only a slight reduction in its ability to promote LAT1 expression at the membrane surface compared with the 529 amino acid wild-type 4F2hc protein. Co-expression of increasingly larger 4F2hc mutants caused a delayed translocation of LAT1. In contrast to the weak effects of 4F2hc truncations on LAT1 expression, surface expression of LAT2 and y+LAT2 was almost completely lost with all truncated heavy chains. Co-expression of LAT1 together with the other light chains did not result in displacement of LAT2 and y+LAT2. The results suggest that extracellular domains of the heavy chain are responsible mainly for recognition of light chains other than LAT1 and that the extracellular domain ensures proper translocation to the plasma membrane.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/bj3550725
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2001
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 7
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    Acid sphingomyelinase promotes SGK1-dependent vascular calcification
    Portland Press Ltd. ; 2021
    In:  Clinical Science Vol. 135, No. 3 ( 2021-02-12), p. 515-534
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 135, No. 3 ( 2021-02-12), p. 515-534
    Abstract: In chronic kidney disease (CKD), hyperphosphatemia is a key factor promoting medial vascular calcification, a common complication associated with cardiovascular events and high mortality. Vascular calcification involves osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs), but the complex signaling events inducing pro-calcific pathways are incompletely understood. The present study investigated the role of acid sphingomyelinase (ASM)/ceramide as regulator of VSMC calcification. In vitro, both, bacterial sphingomyelinase and phosphate increased ceramide levels in VSMCs. Bacterial sphingomyelinase as well as ceramide supplementation stimulated osteo-/chondrogenic transdifferentiation during control and high phosphate conditions and augmented phosphate-induced calcification of VSMCs. Silencing of serum- and glucocorticoid-inducible kinase 1 (SGK1) blunted the pro-calcific effects of bacterial sphingomyelinase or ceramide. Asm deficiency blunted vascular calcification in a cholecalciferol-overload mouse model and ex vivo isolated-perfused arteries. In addition, Asm deficiency suppressed phosphate-induced osteo-/chondrogenic signaling and calcification of cultured VSMCs. Treatment with the functional ASM inhibitors amitriptyline or fendiline strongly blunted pro-calcific signaling pathways in vitro and in vivo. In conclusion, ASM/ceramide is a critical upstream regulator of vascular calcification, at least partly, through SGK1-dependent signaling. Thus, ASM inhibition by repurposing functional ASM inhibitors to reduce the progression of vascular calcification during CKD warrants further study.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    URL: Article
    DOI: 10.1042/CS20201122
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2021
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  • 8
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    Characterization of mouse amino acid transporter B0AT1 (slc6a19)
    Portland Press Ltd. ; 2005
    In:  Biochemical Journal Vol. 389, No. 3 ( 2005-08-01), p. 745-751
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 389, No. 3 ( 2005-08-01), p. 745-751
    Abstract: The mechanism of the mouse (m)B0AT1 (slc6a19) transporter was studied in detail using two electrode voltage-clamp techniques and tracer studies in the Xenopus oocyte expression system. All neutral amino acids induced inward currents at physiological potentials, but large neutral non-aromatic amino acids were the preferred substrates of mB0AT1. Substrates were transported with K0.5 values ranging from approx. 1 mM to approx. 10 mM. The transporter mediates Na+–amino acid co-transport with a stoichiometry of 1:1. No other ions were involved in the transport mechanism. An increase in the extracellular Na+ concentration reduced the K0.5 for leucine, and vice versa. Moreover, the K0.5 values and Vmax values of both substrates varied with the membrane potential. As a result, K0.5 and Vmax values are a complex function of the concentration of substrate and co-substrate and the membrane potential. A model is presented assuming random binding order and a positive charge associated with the ternary [Na+–substrate–transporter] complex, which is consistent with the experimental data.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20050083
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2005
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 9
    Online Resource
    Online Resource
    The heterodimeric amino acid transporter 4F2hc/y+LAT2 mediates arginine efflux in exchange with glutamine
    Portland Press Ltd. ; 2000
    In:  Biochemical Journal Vol. 349, No. 3 ( 2000-08-01), p. 787-795
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 349, No. 3 ( 2000-08-01), p. 787-795
    Abstract: The cationic amino acid arginine, due to its positive charge, is usually accumulated in the cytosol. Nevertheless, arginine has to be released by a number of cell types, e.g. kidney cells, which supply other organs with this amino acid, or the endothelial cells of the blood–brain barrier which release arginine into the brain. Arginine release in mammalian cells can be mediated by two different transporters, y+LAT1 and y+LAT2. For insertion into the plasma membrane, these transporters have to be associated with the type-II membrane glycoprotein 4F2hc [Torrents, Estevez, Pineda, Fernandez, Lloberas, Shi, Zorzano and Palacin (1998) J. Biol. Chem. 273, 32437–32445]. The present study elucidates the function and distribution of y+LAT2. In contrast to y+LAT1, which is expressed mainly in kidney epithelial cells, lung and leucocytes, y+LAT2 has a wider tissue distribution, including brain, heart, testis, kidney, small intestine and parotis. When co-expressed with 4F2hc in Xenopus laevis oocytes, y+LAT2 mediated uptake of arginine, leucine and glutamine. Arginine uptake was inhibited strongly by lysine, glutamate, leucine, glutamine, methionine and histidine. Mutual inhibition was observed when leucine or glutamine was used as substrate. Inhibition of arginine uptake by neutral amino acids depended on the presence of Na+, which is a hallmark of y+LAT-type transporters. Although arginine transport was inhibited strongly by glutamate, this anionic amino acid was only weakly transported by 4F2hc/y+LAT2. Amino acid transport via 4F2hc/y+LAT2 followed an antiport mechanism similar to the other members of this new family. Only preloaded arginine could be released in exchange for extracellular amino acids, whereas marginal release of glutamine or leucine w as observed under identical conditions. These results indicated that arginine has the highest affinity for the intracellular binding site and that arginine release may be the main physiological function of this transporter.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/bj3490787
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2000
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 10
    Online Resource
    Online Resource
    Cystinuria-specific rBAT(R365W) mutation reveals two translocation pathways in the amino acid transporter rBAT-b0,+AT
    Portland Press Ltd. ; 2004
    In:  Biochemical Journal Vol. 377, No. 3 ( 2004-02-01), p. 665-674
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 377, No. 3 ( 2004-02-01), p. 665-674
    Abstract: Apical reabsorption of dibasic amino acids and cystine in kidney is mediated by the heteromeric amino acid antiporter rBAT/b0,+AT (system b0,+). Mutations in rBAT cause cystinuria type A, whereas mutations in b0,+AT cause cystinuria type B. b0,+AT is the catalytic subunit, whereas it is believed that rBAT helps the routing of the rBAT/b0,+AT heterodimeric complex to the plasma membrane. In the present study, we have functionally characterized the cystinuria-specific R365W (Arg365→Trp) mutation of human rBAT, which in addition to a trafficking defect, alters functional properties of the b0,+ transporter. In oocytes, where human rBAT interacts with the endogenous b0,+AT subunit to form an active transporter, the rBAT(R365W) mutation caused a defect of arginine efflux without altering arginine influx or apparent affinities for intracellular or extracellular arginine. Transport of lysine or leucine remained unaffected. In HeLa cells, functional expression of rBAT(R365W)/b0,+AT was observed only at the permissive temperature of 33 °C. Under these conditions, the mutated transporter showed 50% reduction of arginine influx and a similar decreased accumulation of dibasic amino acids. Efflux of arginine through the rBAT(R365W)/b0,+AT holotransporter was completely abolished. This supports a two-translocation-pathway model for antiporter b0,+, in which the efflux pathway in the rBAT(R365W)/b0,+AT holotransporter is defective for arginine translocation or dissociation. This is the first direct evidence that mutations in rBAT may modify transport properties of system b0,+.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/bj20030956
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2004
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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