Abstract
Cationic amino acid transporters (CATs) play a central role in the supply of the substrate L-arginine to intracellular nitric oxide synthases (NOS), the enzymes responsible for the synthesis of nitric oxide (NO). In heart, NO produced by cardiac myocytes has diverse and even opposite effects on myocardial contractility depending on the subcellular location of its production. Approximately a decade ago, using a combination of biophysical and biochemical approaches, we discovered and characterized high- and low-affinity CATs that function simultaneously in the cardiac myocyte plasma membrane. Later on, we reported a negative feedback regulation of NO on the activity of cardiac CATs. In this way, NO was found to modulate its own biosynthesis by regulating the amount of L-arginine that becomes available as NOS substrate. We have recently solved the molecular determinants for this NO regulation on the low-affinity high-capacity CAT-2A. This review highlights some biophysical and biochemical features of L-arginine transporters and their potential relation to cardiac muscle physiology and pathology.
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References
Al-Saleh EA, Wheeler KP (1982) Transport of neutral amino acids by human erythrocytes. Biochim Biophys Acta 684:157–171. https://doi.org/10.1016/0005-2736(82)90001-3
Assreuy J, Cunha FQ, Liew FY, Moncada S (1993) Feedback inhibition of nitric oxide synthase activity by nitric oxide. Br J Pharmacol 108:833–837. https://doi.org/10.1111/j.1476-5381.1993.tb12886.x
Balligand JL, Kelly RA, Marsden PA, Smith TW, Michel T (1993) Control of cardiac muscle cell function by an endogenous nitric oxide signaling system. Proc Natl Acad Sci USA 90:347–351. https://doi.org/10.1073/pnas.90.1.347
Beckman JS, Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol Cell Physiol 271:C1424–C1437. https://doi.org/10.1152/ajpcell.1996.271.5.C1424
Beyer SR, Mallmann RT, Jaenecke I, Habermeier A, Boissel J-P, Closs EI (2013) Identification of cysteine residues in human cationic amino acid transporter hCAT-2A that are targets for inhibition by N-ethylmaleimide. J Biol Chem 288:30411–30419. https://doi.org/10.1074/jbc.M113.490698
Bloch W, Fleischmann BK, Lorke DE, Andressen C, Hops B, Hescheler J, Addicks K (1999) Nitric oxide synthase expression and role during cardiomyogenesis. Cardiovasc Res 43:675–684. https://doi.org/10.1016/S0008-6363(99)00160-1
Bredt DS (2003) Nitric oxide signaling specificity – the heart of the problem. J Cell Sci 116:9–15. https://doi.org/10.1242/jcs.00183
Bredt DS, Snyder SH (1994) Nitric oxide: a physiologic messenger molecule. Annu Rev Biochem 63:175–195. https://doi.org/10.1146/annurev.bi.63.070194.001135
Chen K, Pittman RN, Popel AS (2008) Nitric oxide in the vasculature: Where does it come from and where does it go? A quantitative perspective. Antioxid Redox Signal 10:1185–1198. https://doi.org/10.1089/ars.2007.1959
Closs EI, Albritton LM, Kim JW, Cunningham JM (1993) Identification of a low affinity, high capacity transporter of cationic amino acids in mouse liver. J Biol Chem 268:7538–7544
Closs EI, Gräf P, Habermeier A, Cunningham JM, Förstermann U (1997) Human cationic amino acid transporters hCAT-1, hCAT-2A and hCAT-2B: three related carriers with distinct transport properties. Biochemistry 36:6462–6468. https://doi.org/10.1021/bi962829p
Crow JP, Ischiropoulos H (1996) Detection and quantitation of nitrotyrosine residues in proteins: in vivo marker of peroxynitrite. Methods Enzymol 269:185–194. https://doi.org/10.1016/s0076-6879(96)69020-x
Devés R, Angelo S, Chávez P (1993) N-Ethylmaleimide discriminates between two lysine transport systems in human erythrocytes. J Physiol 468:753–766. https://doi.org/10.1113/jphysiol.1993.sp019799
Devés R, Boyd CAR (1998) Transporters for cationic amino acids in animal cells: discovery, structure, and function. Physiol Rev 78:487–545. https://doi.org/10.1152/physrev.1998.78.2.487
Devés R, Krupka RM (1981) Evidence for a two-state mobile carrier mechanism in erythrocyte choline transport: effects of substrate analogs on inactivation of the carrier by N-ethylmaleimide. J Membr Biol 61:21–30. https://doi.org/10.1007/BF01870749
Ducrocq C, Blanchard B, Pignatelli B, Ohshima H (1999) Peroxynitrite: an endogenous oxidizing and nitrating agent. Cell Mol Life Sci 55:1068–1077. https://doi.org/10.1007/s000180050357
Ferdinandy P, Danial H, Ambrus I, Rothery RA, Schulz R (2000) Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res 87:241–247. https://doi.org/10.1161/01.res.87.3.241
Forray MI, Angelo S, Boyd CAR, Devés R (1995) Transport of nitric oxide synthase inhibitors through cationic amino acid carriers in human erythrocytes. Biochem Pharmacol 50:1963–1968. https://doi.org/10.1016/0006-2952(95)02090-x
Gaston B (1999) Nitric oxide and thiol groups. Biochim Biophys Acta – Bioenerg 1411:323–333 https://doi.org/10.1016/S0005-2728(99)00023-7
Gelpí JL, Kalko SG, Barril X, Cirera J, de la Cruz X, Luque FJ, Orozco M (2001) Classical molecular interaction potentials: improved setup procedure in molecular dynamics simulations of proteins. Proteins 45:428–437. https://doi.org/10.1002/prot.1159
Gross SS, Wolin MS (1995) Nitric oxide: pathophysiological mechanisms. Annu Rev Physiol 57:737–769. https://doi.org/10.1146/annurev.ph.57.030195.003513
Hecker M, Sessa WC, Harris HJ, Anggard EE, Vane JR (1990) The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: cultured endothelial cells recycle L-citrulline to L-arginine. Proc Natl Acad Sci USA 87:8612–8616. https://doi.org/10.1073/pnas.87.21.8612
Heinrich TA, da Silva RS, Miranda KM, Switzer CH, Wink DA, Fukuto JM (2013) Biological nitric oxide signalling: chemistry and terminology. Br J Pharmacol 169:1417–1429. https://doi.org/10.1111/bph.12217
Jungnickel KEJ, Parker JL, Newstead S (2018) Structural basis for amino acid transport by the CAT family of SLC7 transporters. Nat Commun 9:1–12. https://doi.org/10.1038/s41467-018-03066-6
Kakuda DK, Finley KD, Dionne VE, MacLeod CL (1993) Two distinct gene products mediate y+ type cationic amino acid transport in Xenopus oocytes and show different tissue expression patterns. Transgene 1:91–101
Kakuda DK, Finley KD, Maruyama M, MacLeod CL (1998) Stress differentially induces cationic amino acid transporter gene expresión. Biochim Biophys Acta 1414:75–84. https://doi.org/10.1016/s0005-2736(98)00155-2
Kakuda DK, MacLeod CL (1994) Na+-independent transport (uniport) of amino acids and glucose in mammalian cells. J Exp Biol 196:93–108
Kavanaugh MP (1993) Voltage dependence of facilitated arginine flux mediated by the system y+ basic amino acid transporter. Biochemistry 32:5781–5785. https://doi.org/10.1021/bi00073a009
Kavanaugh MP, Wang H, Zhang Z, Zhang W, Wu YN, Dechant E, North RA, Kabat D (1994) Control of cationic amino acid transport and retroviral receptor functions in a membrane protein family. J Biol Chem 269:15445–15450
Kim JW, Closs EI, Albritton LM, Cunningham JM (1991) Transport of cationic amino acids by the mouse ecotropic retrovirus receptor. Nature 352:725–728. https://doi.org/10.1038/352725a0
Kowalczyk L, Ratera M, Paladino A, Bartoccioni P, Errasti-Murugarren E, Valencia E, Portella G, Bial S, Zorzano A, Fita I, Orozco M, Carpena X, Vázquez-Ibar JL, Palacín M (2011) Molecular basis of substrate-induced permeation by an amino acid antiporter. Proc Natl Acad Sci USA 108:3935–3940. https://doi.org/10.1073/pnas.1018081108
Lu X, Zheng R, Gonzalez J, Gaspers L, Kuzhikandathil E, Peluffo RD (2009) L-Lys uptake in giant vesicles from cardiac ventricular sarcolemma: two components of cationic amino acid transport. Biosci Rep 29:271–281. https://doi.org/10.1042/BSR20080159
Massion PB, Feron O, Dessy C, Balligand JL (2003) Nitric oxide and cardiac function: ten years after, and continuing. Circ Res 93:388–398. https://doi.org/10.1161/01.RES.0000088351.58510.21
Morris SM (1992) Regulation of enzymes of urea and arginine synthesis. Annu Rev Nutr 12:81–101. https://doi.org/10.1146/annurev.nu.12.070192.000501
Nathan C (1992) Nitric oxide as a secretory product of mammalian cells. FASEB J 6:3051–3064. https://doi.org/10.1096/fasebj.6.12.1381691
Nawrath H, Wegener JW, Rupp J, Habermeier A, Closs EI (2000) Voltage dependence of L-arginine transport by hCAT-2A and hCAT-2B expressed in oocytes from Xenopus laevis. Am J Physiol Cell Physiol 279:1336–1344. https://doi.org/10.1152/ajpcell.2000.279.5.C1336
Noeh FM, Wenzel A, Harris N, Milakofsky L, Hofford JM, Pell S, Vogel WH (1996) The effects of arginine administration on the levels of arginine, other amino acids and related amino compounds in the plasma, heart, aorta, vena cava, bronchi and pancreas of the rat. Life Sci 58:131–138. https://doi.org/10.1016/S0024-3205(96)80013-0
Orie NN, Vallance P, Jones DP, Moore KP (2005) S-nitroso-albumin carries a thiol-labile pool of nitric oxide, which causes venodilation in the rat. Am J Physiol Heart Circ Physiol 289:916–923. https://doi.org/10.1152/ajpheart.01014.2004
Palacín M, Estévez R, Bertran J, Zorzano A (1998) Molecular biology of mammalian plasma membrane amino acid transporters. Physiol Rev 78:969–1054. https://doi.org/10.1152/physrev.1998.78.4.969
Peluffo RD (2007) L-Arginine currents in rat cardiac ventricular myocytes. J Physiol 580:925–936. https://doi.org/10.1113/jphysiol.2006.125054
Puppi M, Henning SJ (1995) Cloning of the rat ecotropic retroviral receptor and studies of its expression in intestinal tissues. Proc Soc Exp Biol Med 209:38–45. https://doi.org/10.3181/00379727-209-43875
Ramachandran J, Peluffo RD (2017) Threshold levels of extracellular L-arginine that trigger NOS-mediated ROS/RNS production in cardiac ventricular myocytes. Am J Physiol Cell Physiol 312:144–154. https://doi.org/10.1152/ajpcell.00150.2016
Ravi K, Brennan LA, Levic S, Ross PA, Black SM (2004) S-nitrosylation of endothelial nitric oxide synthase is associated with monomerization and decreased enzyme activity. Proc Natl Acad Sci USA 101:2619–2624. https://doi.org/10.1073/pnas.0300464101
Reifenberger MS, Arnett KL, Gatto C, Milanick MA (2008) The reactive nitrogen species peroxynitrite is a potent inhibitor of renal Na-K-ATPase activity. Am J Physiol Renal Physiol 295:1191–1198. https://doi.org/10.1152/ajprenal.90296.2008
Rogers NE, Ignarro LJ (1992) Constitutive nitric oxide synthase from cerebellum is reversibly inhibited by nitric oxide formed from L-arginine. Biochem Biophys Res Commun 189:242–249. https://doi.org/10.1016/0006-291x(92)91550-a
Simmons WW, Closs EI, Cunningham JM, Smith TW, Kelly RA (1996) Cytokines and insulin induce cationic amino acid transporter (CAT) expression in cardiac myocytes. J Biol Chem 271:11694–11702. https://doi.org/10.1074/jbc.271.20.11694
Stein W (1990) Channels, Carriers, and Pumps: An Introduction to Membrane Transport. Academic Press, San Diego
van Haeften TW, Konings CH (1989) Arginine pharmacokinetics in humans assessed with an enzymatic assay adapted to a centrifugal analyzer. Clin Chem 35:1024–1026
Vickroy TW, Malphurs WL (1995) Inhibition of nitric oxide synthase activity in cerebral cortical synaptosomes by nitric oxide donors: evidence for feedback autoregulation. Neurochem Res 20:299–304. https://doi.org/10.1007/BF00969546
White MF, Gazzola GC, Christensen HN (1982) Cationic amino acid transport into cultured animal cells. I. Influx into cultured human fibroblasts. J Biol Chem 257:4443–4449. https://doi.org/10.1016/S0021-9258(18)34742-2
Wu GY, Brosnan JT (1992) Macrophages can convert citrulline into arginine. Biochem J 281:45–48. https://doi.org/10.1042/bj2810045
Xia Y, Tsai AL, Berka V, Zweier JL (1998) Superoxide generation from endothelial nitric-oxide synthase. A Ca2+/calmodulin-dependent and tetrahydrobiopterin regulatory process. J Biol Chem 273:25804–25808. https://doi.org/10.1074/jbc.273.40.25804
Yoshimoto T, Yoshimoto E, Meruelo D (1991) Molecular cloning and characterization of a novel human gene homologous to the murine ecotropic retroviral receptor. Virology 185:10–15. https://doi.org/10.1016/0042-6822(91)90748-z
Zheng R, da Rosa G, Dans PD, Peluffo RD (2020) Molecular determinants for nitric oxide regulation of the murine cationic amino acid transporter CAT-2A. Biochemistry 59:4225–4237. https://doi.org/10.1021/acs.biochem.0c00729
Zhou J, Kim DD, Peluffo RD (2010) Nitric oxide can acutely modulate its biosynthesis through a negative feedback mechanism on L-arginine transport in cardiac myocytes. Am J Physiol Cell Physiol 299:230–239. https://doi.org/10.1152/ajpcell.00077.2010
Zhou J, Peluffo RD (2010) D-enantiomers take a close look at the functioning of a cardiac cationic L-amino acid transporter. Biophys J 99:3224–3233. https://doi.org/10.1016/j.bpj.2010.09.025
Acknowledgements
Dr. Pablo Dans’ help in making the artwork for figure 3 is gratefully acknowledged. R.D. Peluffo is an established investigator from the Program for the Development of the Basic Sciences (PEDECIBA, Uruguay) and the Uruguayan National Agency for Research and Innovation (ANII).
Funding
This work was supported over the years by the National Heart, Lung, and Blood Institute (Grant R01-HL-076392) and by a Scientist Development Grant from the American Heart Association, National branch.
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Peluffo, R.D. Cationic amino acid transporters and their modulation by nitric oxide in cardiac muscle cells. Biophys Rev 13, 1071–1079 (2021). https://doi.org/10.1007/s12551-021-00870-1
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DOI: https://doi.org/10.1007/s12551-021-00870-1