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1 Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093–0725, USA Email: xiyuan{at}ucsd.edu
For many of us, the term ‘L-arginine’ immediately conjures up the concept of nitric oxide (NO) production. Indeed, L-arginine is the precursor for production of vasodilatory NO. However, in many organs and tissues, arginine is also required for protein biosynthesis and release of hormones. In addition it is a precursor molecule for a number of proteins other than NO that regulate cardiac function and a precursor for producing creatine, agmatine and polyamines (spermine and putrescine). In the heart, altered arginine supply and NO production regulate cardiac contractility and cardiomyocyte proliferation (and/or apoptosis), which may contribute to normal cardiac function and, pathologically, to cardiac hypertrophy.
Endogenous biosynthesis in the kidney and small intestine represents the most important source of arginine, so much so that arginine is not an essential dietary amino acid for healthy adults. With the exception of the kidney and small intestine, most tissues lack the biochemical machinery for the de novo synthesis of arginine from intracellular ornithine or citrulline pools. Therefore, bioavailability of circulating arginine and its subsequent transport across the plasma membrane into different cell types may become rate limiting for the enzymatic reactions which use arginine as a substrate.
Other than gas and water, very few ions and molecules can passively diffuse across the plasma membrane due to restrictions of size or charge and lipid solubility. Transport of ions and small molecules occurs via channel proteins with a built-in ion selectivity filter and transporter proteins which transport ions or small molecules against their (electro)chemical gradient. However, amino acids are too large to flow through ‘conventional’ ion channels and instead employ transport proteins for their transmembrane transportation. Carrier proteins for cationic amino acids have been described in different cell types and tissues (Verrey et al. 2004). They belong to the solute carrier family 7 (SLC7) gene family, have overlapping substrate specificities, and can be distinguished by their requirement for the co- and counter-transport of inorganic ions. The b+, b0,+, B0,+ and y+L systems all mediate high-affinity cationic and neutral amino acid transport (Closs et al. 2004). However, system y+ transporters are highly selective for cationic L-amino acids. These Na+-independent transport proteins, known as CATs (cationic amino acid transporters), are encoded by high-affinity and low-affinity SLC7A1-4 genes, with CAT-2A (SLC7A2 gene) being the least selective for arginine (Km 2–5 mM). L-Arginine flux studies revealed that CAT activity varies between subunits based not only on substrate affinity, but also on kinetics of transport and sensitivity to trans-stimulation (Closs et al. 1997; Rotmann et al. 2004). However, these studies did not take into account the regulation of arginine transport by membrane potential changes as originally proposed by Kavanaugh (1993). Consequently, Nawrath et al. (2000) demonstrated that CAT-2A and CAT-2B proteins produce inward and outward currents which are dependent on the arginine concentration gradient and membrane potential.
CAT-2A proteins are highly expressed in the liver, and, to a lesser extent, in the pancreas, skeletal muscle, heart and vascular smooth muscle cells. However, L-arginine currents have not been characterized extensively in native cells where CAT-2A proteins are expressed. In pancreatic 
-cells, L-arginine induces a small current whose amplitude is decreased by membrane depolarization, like that shown for CAT-2A currents in oocytes (Nawrath et al. 2000). In this issue of The Journal of Physiology, Peluffo (2007) describes the currents produced by L-arginine stimulation in native rat ventricular myocytes. The key observation is that cardiac L-arginine current density is up to eight times larger in cardiac myocytes than in pancreatic -cells. Furthermore, L-lysine and L-ornithine, but not D-arginine, produced similar currents, suggesting that the effect is stereospecific for cationic L-amino acids. Based on saturation kinetics (membrane potential-dependent K0.5) and voltage dependence, the currents are believed to resemble that produced by CAT-2A proteins in oocytes. The increased L-arginine uptake correlated with enhanced NO production, further suggesting that L-arginine is the charge carrier involved.
You may ask what this adds to our understanding of the physiological role of NO in cardiac (dys)function. First, altered NO bioavailability has been ascribed an important role in congestive heart failure. More specifically, ventricular and systemic L-arginine uptake is significantly reduced in patients with congestive heart failure (Kaye et al. 2002); not surprisingly, oral or intravenous treatment with arginine improves the outcome of patients with congestive heart failure (Koifman et al. 1995). Secondly, interleukin-1 and interferon-
stimulate CAT-2A and CAT-2B expression and L-arginine uptake in neonatal cardiomyocytes (Simmons et al. 1996). Thirdly, tetrahydrobiopterin enhances cardiomyocyte NO synthesis by augmenting L-arginine uptake, presumably by modulating CAT-2A expression (Schwartz et al. 2001). Finally, the change in membrane potential that occurs constantly during the cardiac excitation–contraction coupling (or contraction–relaxation cycling) regulates L-arginine uptake or influx through CATs in cardiomyocytes. Peluffo's findings provide important information regarding the mechanics of L-arginine transport into cardiomyocytes and the electrophysiological properties of the transporters involved. Because NO has a tremendous protective effect on the myocardium, it is important that we understand not only how to promote its production or concentration via intracellularly produced substrate (i.e. L-arginine), but also that we address another critical limiting factor in cardiac NO production: effective accessing of circulating (and/or locally produced) L-arginine to the intracellular milieu in the effector cells.
References
Closs EI, Simon A, Vékony N & Rotmann A (2004). J Nutr 134, 2752S–2759S.
Kavanaugh MP (1993). Biochemistry 32, 5781–5785.[CrossRef][Medline]
Kaye DM, Parnell MM & Ahlers BA (2002). Circ Res 91, 1198–1203.
Koifman B, Wollman Y, Bogomolny N, Chernichowsky T, Finkelstein A, Peer G, Scherez J, Blum M, Laniado S, Iaina A & Keren G (1995). J Am Coll Cardiol 26, 1251–1256.[Abstract]
Nawrath H, Wegener JW, Rupp J, Habermeier A & Closs EI (2000). Am J Physiol Cell Physiol 279, C1336–C1344.
Peluffo RD (2007). J Physiol 580, 925–936.
Rotmann A, Closs EI, Liewald JF & Nawrath H (2004). Biochim Biophys Acta 1660, 138–143.[Medline]
Schwartz IF, Schwartz D, Wollman Y, Chernichowski T, Blum M, Levo Y & Iaina A (2001). J Lab Clin Med 137, 356–362.[CrossRef][Medline]
Simmons WW, Closs EI, Cunningham JM, Smith TW & Kelly RA (1996). J Biol Chem 271, 11694–11702.
Verrey F, Closs EI, Wagner CA, Palacin M, Endou H & Kanai Y (2004). Pflugers Arch 447, 532–542.[CrossRef][Medline]
Related Article
J. Physiol. 2007 580: 925-936.
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