EDITORIAL FOCUS
System N in eNdothelium

D. Michael Shasby

Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa 52242


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AMINO ACIDS ARE THE ELEMENTS of protein structure, and their side chains largely determine the function of the proteins they constitute. Some amino acids, such as glycine and glutamate, are important neurotransmitters. Some are metabolized to signaling molecules such as glutamate to gamma -aminobutyric acid (GABA) and arginine to nitric oxide (NO). Amino acids participate in the urea cycle and NH4 metabolism that are essential to hepatic and renal function. Glutathione is a tripeptide that is important to redox balance and participates in amino acid transport. Several families of transporters exist to facilitate the movement of amino acids across the cell membrane for these and other purposes.

Historically, the transporters have been defined by substrate specificities, thermodynamics, inhibitor profiles, cotransport of ions, pH sensitivity, organ and cell distribution, and similar properties (1). Groups of transporters with similar properties were aggregated into systems. Individual amino acids are transported by more than one system, and the phenotype of different systems drifts across different cells. Early in the 1990s, individual transporters began to be identified at the molecular level. One of the first was the GABA transporter, which removes GABA from the synaptic cleft and utilizes the energy of the Na gradient across the cell membrane to transport against a high concentration gradient (6, 13). Identification of other neurotransmitter amino acid transporters occurred rapidly during the 1990s with two additional GABA transporters (GAT-1 to GAT-3), a betaine/GABA transporter, a taurine transporter, and two glycine transporters. Transport by all of these is dependent on both sodium and chloride, which move in opposite directions across the cell membrane. GABA is the principal inhibitory neurotransmitter. Inhibition of the GAT-1 transporter allows GABA to persist in the synaptic cleft and has anticonvulsant effects (1).

Identification of the GABA transporter was followed closely by identification of the first cationic amino acid transporter that also utilizes the energy of the Na gradient to transport cationic and neutral amino acids into the cell (10, 19). Some of the cationic transporters are particularly relevant to lung physiology. The cationic amino acid transporters include CAT-1 to CAT-4. Tumor necrosis factor (TNF) increases endothelial and vascular smooth muscle cell NO synthesis, and this is dependent on increased arginine transport into the cells. The increased arginine transport is accomplished by TNF stimulating increases in expression of CAT-2 (16, 17). A similar increase in CAT-2 expression occurs in TNF-stimulated macrophages that use NO for microbicidal and other activities (2). Nitric oxide synthase inhibitors are themselves amino acids. Some of them are transported by the ATB0,+ transporter (7). This transporter is found in the apical surface of epithelial cells in the gastrointestinal tract and may also be expressed in lung alveolar epithelial cells (8).

The study by Sakurai et al., one of the current articles in focus (Ref. 15, see p. L1192 in this issue) describes histidine transport in rat lung microvascular endothelial cells. Their data indicate histidine is transported by both system L and system N. System L transports neutral amino acids independent of Na and mediates exchange, not active transport, against a concentration gradient. It is expressed widely, and the transporter is composed of the LAT-1 protein and the 4F2hc molecule. The characteristics of transport are determined by the LAT-1 protein while localization to the cell membrane is determined by the 4F2hc molecule. In T cells, expression of both proteins increases with activation (12). System L is one of several systems that are composed of heterodimers, and these transporters were recently reviewed (18).

Sakurai et al. (15) also identified system N transport of histidine into the lung microvessel cells. System N and system A mediate Na-dependent transport of neutral amino acids. Classically, system A had broader substrate specificity and a wider distribution while system N was more specific for glutamine, arginine, and histidine and was limited to brain and liver (13). More recently, it has become evident that system A and system N are from a single gene family with variant expression in different tissues. Of the three different system A transporters that have been identified (SAT-1 to SAT-3), SAT-2 would be the one most likely relevant to endothelium (3). It has broad tissue distribution, whereas SAT-1 is in brain and SAT-3 is in liver.

However, on the basis of the inhibitor profile, the Na-dependent transporter that Sakurai et al. (15) identified seems to belong to the system N group. Three system N transporters have been identified. SN1 is localized in brain and liver and was identified primarily as a glutamine transporter (4). SN2 has a broader tissue expression, including lung, and a remarkable expression in stomach (11). The stomach expression was postulated to relate to the necessity of enterochromaffin cells of the stomach to release histamine to stimulate parietal cell secretion of hydrogen (14). Because histidine is the precursor to histamine, system N transport of histidine into the enterochromaffin cells would be needed. SN3 is the most recently identified member of the N family with sequence homology to both the system A and system N transporters. It is expressed in liver, muscle, kidney, and pancreas (5).

It is not evident which system N transporter Sakurai et al. (15) have identified. SN2 is expressed in lung, but not in many other tissues. Is the expression specific to lung or to endothelium? If it is specific to endothelium, then we might expect a broader tissue expression unless its activity is very specific to lung endothelium.

Sakurai et al. (15) speculate that this transporter may be important in delivering histidine to the lung for histamine production. It is not likely that the lung endothelium is a strict barrier to the paracellular diffusion and convection of histidine. Hence, it is more likely that the function of the system N transporter relates to the physiology of the endothelial cells themselves. Cerebral microvascular endothelial cells do not metabolize histidine to histamine (9). However, they do take up extracellular histamine. Could the histidine transporter identified by Sakurai et al. function to take up histamine and stop receptor activation analogously to what the GABA receptor does in the brain? Or is it more likely that it functions primarily as a glutamine transporter, contributing to glutathione metabolism and protection of the cells against oxidant stress? The physiological roles of endothelial amino acid transporters are poorly defined, and the field offers fruitful opportunities with abundant molecular tools.


    FOOTNOTES

Address for reprint requests and other correspondence: D. M. Shasby, Dept. of Internal Medicine, Univ. of Iowa College of Medicine, Iowa City, IA 52242 (E-mail: shasby{at}blue.weeg.uiowa.edu).

10.1152/ajplung.00046.2002


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Am J Physiol Lung Cell Mol Physiol 282(6):L1190-L1191
1040-0605/02 $5.00 Copyright © 2002 the American Physiological Society




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