L-Arginine and Cardioactive Arginine Derivatives as Substrates and Inhibitors of Human and Mouse NaCT/Nact
The uptake transporter NaCT (gene symbol <i>SLC13A5</i>) is expressed in liver and brain and important for energy metabolism and brain development. Substrates include tricarboxylic acid cycle intermediates, e.g., citrate and succinate. To gain insights into the substrate spectrum of NaCT...
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MDPI AG
2022-03-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/12/4/273 |
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| author | Daniela B. Surrer Martin F. Fromm Renke Maas Jörg König |
| author_facet | Daniela B. Surrer Martin F. Fromm Renke Maas Jörg König |
| author_sort | Daniela B. Surrer |
| collection | DOAJ |
| description | The uptake transporter NaCT (gene symbol <i>SLC13A5</i>) is expressed in liver and brain and important for energy metabolism and brain development. Substrates include tricarboxylic acid cycle intermediates, e.g., citrate and succinate. To gain insights into the substrate spectrum of NaCT, we tested whether arginine and the cardioactive L-arginine metabolites asymmetric dimethylarginine (ADMA) and L-homoarginine are also transported by human and mouse NaCT/Nact. Using HEK293 cells overexpressing human or mouse NaCT/Nact we characterized these substances as substrates. Furthermore, inhibition studies were performed using the arginine derivative symmetric dimethylarginine (SDMA), the NaCT transport inhibitor BI01383298, and the prototypic substrate citrate. Arginine and the derivatives ADMA and L-homoarginine were identified as substrates of human and mouse NaCT. Transport of arginine and derivatives mediated by human and mouse NaCT were dose-dependently inhibited by SDMA. Whereas BI01383298 inhibited only human NaCT-mediated citrate uptake, it inhibits the uptake of arginine and derivatives mediated by both human NaCT and mouse Nact. In contrast, the prototypic substrate citrate inhibited the transport of arginine and derivatives mediated only by human NaCT. These results demonstrate a so far unknown link between NaCT/Nact and L-arginine and its cardiovascular important derivatives. |
| first_indexed | 2024-03-09T13:19:30Z |
| format | Article |
| id | doaj.art-7d87a520d14c48ce99eb537c8cd85cb6 |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-09T13:19:30Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-7d87a520d14c48ce99eb537c8cd85cb62023-11-30T21:31:31ZengMDPI AGMetabolites2218-19892022-03-0112427310.3390/metabo12040273L-Arginine and Cardioactive Arginine Derivatives as Substrates and Inhibitors of Human and Mouse NaCT/NactDaniela B. Surrer0Martin F. Fromm1Renke Maas2Jörg König3Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, GermanyInstitute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, GermanyInstitute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, GermanyInstitute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, GermanyThe uptake transporter NaCT (gene symbol <i>SLC13A5</i>) is expressed in liver and brain and important for energy metabolism and brain development. Substrates include tricarboxylic acid cycle intermediates, e.g., citrate and succinate. To gain insights into the substrate spectrum of NaCT, we tested whether arginine and the cardioactive L-arginine metabolites asymmetric dimethylarginine (ADMA) and L-homoarginine are also transported by human and mouse NaCT/Nact. Using HEK293 cells overexpressing human or mouse NaCT/Nact we characterized these substances as substrates. Furthermore, inhibition studies were performed using the arginine derivative symmetric dimethylarginine (SDMA), the NaCT transport inhibitor BI01383298, and the prototypic substrate citrate. Arginine and the derivatives ADMA and L-homoarginine were identified as substrates of human and mouse NaCT. Transport of arginine and derivatives mediated by human and mouse NaCT were dose-dependently inhibited by SDMA. Whereas BI01383298 inhibited only human NaCT-mediated citrate uptake, it inhibits the uptake of arginine and derivatives mediated by both human NaCT and mouse Nact. In contrast, the prototypic substrate citrate inhibited the transport of arginine and derivatives mediated only by human NaCT. These results demonstrate a so far unknown link between NaCT/Nact and L-arginine and its cardiovascular important derivatives.https://www.mdpi.com/2218-1989/12/4/273uptakearginine derivativesL-argininecardioactive arginine metabolitestransport inhibition |
| spellingShingle | Daniela B. Surrer Martin F. Fromm Renke Maas Jörg König L-Arginine and Cardioactive Arginine Derivatives as Substrates and Inhibitors of Human and Mouse NaCT/Nact Metabolites uptake arginine derivatives L-arginine cardioactive arginine metabolites transport inhibition |
| title | L-Arginine and Cardioactive Arginine Derivatives as Substrates and Inhibitors of Human and Mouse NaCT/Nact |
| title_full | L-Arginine and Cardioactive Arginine Derivatives as Substrates and Inhibitors of Human and Mouse NaCT/Nact |
| title_fullStr | L-Arginine and Cardioactive Arginine Derivatives as Substrates and Inhibitors of Human and Mouse NaCT/Nact |
| title_full_unstemmed | L-Arginine and Cardioactive Arginine Derivatives as Substrates and Inhibitors of Human and Mouse NaCT/Nact |
| title_short | L-Arginine and Cardioactive Arginine Derivatives as Substrates and Inhibitors of Human and Mouse NaCT/Nact |
| title_sort | l arginine and cardioactive arginine derivatives as substrates and inhibitors of human and mouse nact nact |
| topic | uptake arginine derivatives L-arginine cardioactive arginine metabolites transport inhibition |
| url | https://www.mdpi.com/2218-1989/12/4/273 |
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