Regulation of amino acid transport at the plasma membrane represents an important point of control in the overall metabolism of these nutrients. A thorough understanding of amino acid transport liver, both normal and diseased, is essential because of the central role of this tissue in amino acid metabolism. By studying the regulation of neutral amino acid transport in isolated rat hepatocytes and the hepatoma cell, HTC, we will gain insight into the mechanisms of cellular control. Specifically, we seek to understand the stimulation of a recently discovered transport agency termed, System T. This process appears to have some preference for aromatic amino acids, but transports other neutral amino acids as well. Its activity increases with time during the initial 48 hr of rat hepatocyte primary cultures, while most of the other neutral amino acid transport systems decrease in activity. This apparent regulation of System T occurs in the absence of exogenous serum or hormones and in the presence of amino acids, thus separating it from previously recognized forms of transport control. Our interest in System T is to compare its regulatory properties with hormonal and adaptive control in an attempt to formulate a general description of cellular control of transport. Detailed knowledge about System T and its regulation may be critical to the understanding of such disease states as Hartnup's disease and blue diaper syndrome. In addition, we intend to investigate the process of adaptive control of System A in both normal hepatocytes and HTC hepatoma cells. Adaptive control, observed as an enhancement in transport activity after starvation of the cells for amino acids, is generally considered to be the result of a derepression of the synthesis of one or more of the proteins necessary for translocation to occur. These studies will allow us to contrast regulation of amino acid transport in both normal and transformed cells. Beyond this comparison, the proposed research represents the first phase of a long-term program aimed at explaining adaptive control in molecular terms. We suggest that an understanding of the regulation governing transport in eukaryotic cells may, in fact, provide insight into the control of other cellular processes. In an analogous situation, the regulation of amino acid transport and amino acid biosynthesis in Escherichia coli appear to operate on similar principles.
NIH ExPorter
NIH ExPorter