SLC Solute Carrier Transporters and Neurodegenerative Disorders: Drawing Attention to Cationic Amino Acid Transporters 1 and 2

Member 4 of human solute carrier family 7 (SLC7A4) exhibits significant sequence homology with the SLC7 subfamily of human cationic amino acid transporters (hCATs) [Sperandeo, Borsani, Incerti, Zollo, Rossi, Zuffardi, Castaldo, Taglialatela, Andria and Sebastio (1998) Genomics 49, 230–236]. It is therefore often referred to as hCAT-4 even though no convincing transport activity has been shown for this protein. We expressed SLC7A4 in Xenopus laevis oocytes, but could not detect any transport activity for cationic, neutral or anionic amino acids or for the polyamine putrescine. In addition, human glioblastoma cells stably overexpressing a fusion protein between SLC7A4 and the enhanced green fluorescent protein (EGFP) did not exhibit an increased transport activity for l-arginine. The lack of transport activity was not due to a lack of SLC7A4 protein expression in the plasma membrane, as in both cell types SLC7A4-EGFP exhibited a similar subcellular localization and level of protein expression as functional hCAT-EGFP proteins. The expression of SLC7A4 can be induced in NT2 teratocarcinoma cells by treatment with retinoic acid. However, also for this endogenously expressed SLC7A4, we could not detect any transport activity for l-arginine. Our data demonstrate that the expression of SLC7A4 in the plasma membrane is not sufficient to induce an amino acid transport activity in X. laevis oocytes or human cells. Therefore, SLC7A4 is either not an amino acid transporter or it needs additional (protein) factor(s) to be functional.

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Cationic Amino Acid Transporters (CATs)

Pharmaceutical Biotechnology - Membrane Transporters as Drug Targets ◽

10.1007/0-306-46812-3_8 ◽

2005 ◽

pp. 229-249 ◽

Cited By ~ 3

Author(s):

Ellen I. Closs ◽

Petra Gräf

Keyword(s):

Amino Acid ◽

Amino Acid Transporters ◽

Cationic Amino Acid

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Na(+)-independent transport (uniport) of amino acids and glucose in mammalian cells.

Journal of Experimental Biology ◽

10.1242/jeb.196.1.93 ◽

1994 ◽

Vol 196 (1) ◽

pp. 93-108

Author(s):

D K Kakuda ◽

C L MacLeod

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Mammalian Cells ◽

Glucose Transporter ◽

Sequence Similarity ◽

Amino Acid Sequence Similarity ◽

Amino Acid Transporters ◽

Cationic Amino Acid ◽

Transporter Family ◽

Share Amino Acid Sequence

Recent advances have made possible the isolation of the genes and their cDNAs encoding Na(+)-independent amino acid transporters. Two classes of amino acid 'uniporters' have been isolated. One class contains the mCAT (murine cationic amino acid transporter) gene family that encodes proteins predicted to span the membrane 12-14 times and exhibits structural properties similar to the GLUT (glucose transporter) family and to other well-known transporters. The other class consists of two known genes, rBAT (related to B system amino acid transporters) and 4F2hc, that share amino acid sequence similarity with alpha-amylases and alpha-glucosidases. They are type II glycoproteins predicted to span the membrane only once, yet they mediate the Na(+)-independent transport of cationic and zwitterionic amino acids in Xenopus oocytes. Mutations in the human rBAT gene have been identified by Palacín and his co-workers in several families suffering from a heritable form of cystinuria. This important finding clearly establishes a key role for rBAT in cystine transport. The two classes of amino acid transporters are compared with the well-studied GLUT family of Na(+)-independent glucose transporters.

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Cationic amino acid transporters and their modulation by nitric oxide in cardiac muscle cells

Biophysical Reviews ◽

10.1007/s12551-021-00870-1 ◽

2021 ◽

Author(s):

R. Daniel Peluffo

Keyword(s):

Nitric Oxide ◽

Amino Acid ◽

Cardiac Muscle ◽

Muscle Cells ◽

Amino Acid Transporters ◽

Cardiac Muscle Cells ◽

Cationic Amino Acid

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Nitric oxide can acutely modulate its biosynthesis through a negative feedback mechanism on l-arginine transport in cardiac myocytes

AJP Cell Physiology ◽

10.1152/ajpcell.00077.2010 ◽

2010 ◽

Vol 299 (2) ◽

pp. C230-C239 ◽

Cited By ~ 10

Author(s):

Jiaguo Zhou ◽

David D. Kim ◽

R. Daniel Peluffo

Keyword(s):

Nitric Oxide ◽

Amino Acid ◽

Cardiac Myocytes ◽

Amino Acid Transporters ◽

No Production ◽

Cardiac Muscle Cells ◽

No Donor ◽

Rat Cardiomyocytes ◽

Cationic Amino Acid ◽

Intervention Point

Nitric oxide (NO) plays a central role as a cellular signaling molecule in health and disease. In the heart, NO decreases the rate of spontaneous beating and the velocity and extent of shortening and accelerates the velocity of relengthening. Since the cationic amino acid l-arginine (l-Arg) is the substrate for NO production by NO synthases (NOS), we tested whether the transporters that mediate l-Arg import in cardiac muscle cells represent an intervention point in the regulation of NO synthesis. Electrical currents activated by l-Arg with low apparent affinity in whole cell voltage-clamped rat cardiomyocytes were found to be rapidly and reversibly inhibited by NO donors. Radiotracer uptake studies performed on cardiac sarcolemmal vesicles revealed the presence of high-affinity/low-capacity and low-affinity/high-capacity components of cationic amino acid transport that were inhibited by the NO donor S-nitroso- N-acetyl-dl-penicillamine. NO inhibited uptake in a noncompetitive manner with Ki values of 275 and 827 nM for the high- and low-affinity component, respectively. Fluorescence spectroscopy experiments showed that millimolar concentrations of l-Arg initially promoted and then inhibited the release of endogenous NO in cardiomyocytes. Likewise, l-Arg currents measured in cardiac myocytes voltage clamped in the presence of 460 nM free intracellular Ca2+, a condition in which a Ca-CaM complex should activate endogenous NO production, showed fast activation followed by inhibition of l-Arg transport. The NOS inhibitor N-nitro-l-arginine methyl ester, but not blockers of downstream reactions, specifically removed this inhibitory component. These results demonstrate that NO acutely regulates its own biosynthesis by modulating the availability of l-Arg via cationic amino acid transporters.

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