Publications

• The prognostic biomarker L-homoarginine is a substrate of the cationic amino acid transporters CAT1, CAT2A and CAT2B.

  Chafai A., Fromm M.F., Koenig J., Maas R.

  Low plasma concentration of L-homoarginine is an independent predictor of cardiovascular events and total mortality. Experimental data indicate that supplementation of L-homoarginine may have protective effects. We aimed to elucidate the mechanisms involved in the cellular uptake of L-homoarginine ... >> More

  Low plasma concentration of L-homoarginine is an independent predictor of cardiovascular events and total mortality. Experimental data indicate that supplementation of L-homoarginine may have protective effects. We aimed to elucidate the mechanisms involved in the cellular uptake of L-homoarginine, which are little understood, so far. Using human embryonic kidney (HEK293) cell lines stably overexpressing the human cationic amino acid transporters CAT1 [solute carrier family 7 (SLC7A1)], CAT2A (SLC7A2A) or CAT2B (SLC7A2B) we assessed the transport kinetics of L-homoarginine and interactions with the CAT substrates L-arginine and asymmetric dimethylarginine (ADMA). Significant uptake of L-homoarginine was observed for all three CATs with apparent K_M-values of 175 ± 7 µM for CAT1 and 523 ± 35 µM for CAT2B. Saturation of CAT2A-mediated L-homoarginine uptake could not be reached. Uptake of L-homoarginine by any of the three CATs could be inhibited by L-arginine and ADMA. Significant inhibition of CAT1-mediated uptake of L-homoarginine by L-arginine already occurred in the physiological concentration range. Taken together these data demonstrate that L-homoarginine is a substrate of CAT1, CAT2A and CAT2B and that CAT1 is a key site with regard to physiological relevance and interactions with related substrates such as L-arginine. << Less

  Sci. Rep. 7:4767-4767(2017) [PubMed] [EuropePMC]

• Transport of cationic amino acids by the mouse ecotropic retrovirus receptor.

  Kim J.W., Closs E.I., Albritton L.M., Cunningham J.M.

  Susceptibility of rodent cells to infection by ecotropic murine leukaemia viruses (MuLV) is determined by binding of the virus envelope to a membrane receptor that has multiple membrane-spanning domains. Cells infected by ecotropic MuLV synthesize envelope protein, gp70, which binds to this recept ... >> More

  Susceptibility of rodent cells to infection by ecotropic murine leukaemia viruses (MuLV) is determined by binding of the virus envelope to a membrane receptor that has multiple membrane-spanning domains. Cells infected by ecotropic MuLV synthesize envelope protein, gp70, which binds to this receptor, thereby preventing additional infections. The consequences of envelope-MuLV receptor binding for the infected host cell have not been directly determined, partly because the cellular function of the MuLV receptor protein is unknown. Here we report a coincidence in the positions of the first eight putative membrane-spanning domains found in the virus receptor and in two related proteins, the arginine and histidine permeases of Saccharomyces cerevisiae (Fig. 1), but not in any other proteins identified by computer-based sequence comparison of the GenBank data base. Xenopus oocytes injected with receptor-encoding messenger RNA show increased uptake of L-arginine, L-lysine and L-ornithine. The transport properties and the expression pattern of the virus receptor behave in ways previously attributed to y+, the principal transporter of cationic L-amino acids in mammalian cells. << Less

  Nature 352:725-728(1991) [PubMed] [EuropePMC]

  This publication is cited by 3 other entries.

• The renal transport protein OATP4C1 mediates uptake of the uremic toxin asymmetric dimethylarginine (ADMA) and efflux of cardioprotective L-homoarginine.

  Taghikhani E., Maas R., Fromm M.F., Koenig J.

  Elevated plasma concentrations of the uremic toxin asymmetrical dimethylarginine (ADMA) and low plasma concentrations of L-homoarginine are independently associated with cardiovascular events and total mortality. Enzymes degrading ADMA [dimethylaminohydrolase 1 (DDAH1)] and synthesizing L-homoargi ... >> More

  Elevated plasma concentrations of the uremic toxin asymmetrical dimethylarginine (ADMA) and low plasma concentrations of L-homoarginine are independently associated with cardiovascular events and total mortality. Enzymes degrading ADMA [dimethylaminohydrolase 1 (DDAH1)] and synthesizing L-homoarginine [L-arginine:glycine amidinotransferase (AGAT)] are expressed in human proximal tubule cells. So far, it is not known which transport protein in the basolateral membrane of proximal tubule cells is mediating the uptake of ADMA into the cells for subsequent degradation or the export of intracellularly synthesized L-homoarginine. One study suggested that the uptake transporter OATP4C1 (gene symbol SLCO4C1) may be involved in the transport of ADMA and other uremic toxins. OATP4C1 is a member of the SLCO/SLC21 family of solute carriers, localized in the basolateral membrane of human proximal tubule cells. By using stably-transfected HEK cells overexpressing human OATP4C1, we demonstrate that ADMA and L-homoarginine are substrates of OATP4C1 with Km values of 232.1 μM and 49.9 μM, respectively. ADMA and the structurally related uremic toxin SDMA (100 μM) inhibited OATP4C1-mediated L-homoarginine uptake (P < 0.01), whereas other tested uremic toxins such as urea and p-cresyl sulfate have no effect on OATP4C1-mediated transport. Preloading experiments (300 μM for 60 min) with subsequent efflux studies revealed that OATP4C1 also facilitates efflux e.g. of L-homoarginine. Both ADMA and L-homoarginine are substrates of human OATP4C1. Because proximal tubule cells are one site of ADMA metabolism and L-homoarginine synthesis, we postulate a protective role of OATP4C1 by mediating uptake of ADMA from and export of L-homoarginine into the systemic circulation. << Less

  PLoS ONE 14:e0213747-e0213747(2019) [PubMed] [EuropePMC]

  This publication is cited by 2 other entries.