MAMMALIAN AMINO ACID TRANSPORT Mechanisms and Control MAMMALIAN AMINO ACID TRANSPORT Mechanisms and Control Edited by Michael S. Kilberg UniversityofFlorida Gainesville,Florida and Dieter Haussinger MedizinischeUniversitiitsklinik Freiburgim Breisgau, Germany Springer Science+Business Media, LLC Library of Congress Cataloging in Publication Data Mammalian amino acid transport: mechanisms and control /edited by Michael S. Kilberg and Dieter Haussinger. p. em. Includes bibliographical references and index. 1. Amino acids-Physiological lransport-Congresscs. I. Kilbcrg, Michael S. II. Haussinger, D. (Dieter), date. QP561.M35 1993 92-37711 599'.0875-dc20 CIP Cover art courtesy of Cell Press, Cambridge, Massachusetts. From K. E. Smith etal., 1992, "Cloning and Expression ofa Glycine Transporter Reveal Colocalization with NMDA Receptors," Neuron, 8:927-935. ProceedingsofaGermanSocietyofBiologicalChemistryconferenceon CoordinateRegulationbetweenTransportand MetabolismofGlutamine,Glutamate, andGamma-GlutamylCompounds,held May 13-16,1990, inTitisee,Germany ISBN978-1-4899-1163-6 ISBN978-1-4899-1161-2(eBook) DOI10.1007/978-1-4899-1161-2 © SpringerScience+BusinessMediaNewYork1992 OriginallypublishedbyPlenumPress,NewYorkin1992. Softcoverreprintofthehardcover1stedition 1992 Allrights reserved Nopartofthis bookmaybe reproduced,storedinaretrievalsystem,ortransmittedin anyform orbyany means,electronic,mechanical,photocopying,microfilming, record ing,orotherwise,withoutwrittenpermissionfrom the Publisher FOREWORD Amino acid transport is a part of each of two larger subjects, amino acid metabolism and the biomembrane transport of various .small molecules and ions. Nevertheless in this volume we treat amino acid transport as more than a fragment of eitherofthesetwolargersubjects. Amorecomprehensiveapproach isjustified whenwe remember two historic and ongoing aspects of the title subject. First,amino acid transport had its beginning and acquired a distinct momentum (even if somewhat interrupted from 1913 until about 1945) as amino acid metabolism with the central and pioneer work of Van Slyke and Meyer in 1913. The reviews in this volume will show that it steadily becomes a larger aspect of amino acid metabolism, broadly perceived. These chapters will show for how many organelles, cells, tissues, organs and organ systems, the transmembrane compartmentations and flows of amino acids play very large parts in their fundamental biological relations. The authors here are tending collectively to evaluate an understanding of amino acid flows across biomernbranes, and the regulation of these flows, as necessary to an ultimate understandingofthefull rangeofdevelopmentand metabolism. Suchan understanding goesfar beyondthe purelysubstrate-destabilizingcontributionsby enzymes,whichhave often been arbitrarily limited to that conceptualentity,"the cell", and which for solong a splendid time had most of biochemical research attention. Secondly, the title interest had another beginning, which it embraced tightly for at least two decades and to which it steadily returns. This beginning encompassed the full range of the phenomenon of the membrane transport of small molecules and ions, whether organic or inorganic. The historic selection of the amino acids for that attack arosenotsomuch fromtheiruniquebiologicalinterestasfromtheadvantagestheyoffer for such studies through their wide ranges of structure, shape, configuration, and distribution of charge and polarity. (An attendant tragedy is the circumstance that probably half of the biological world blinds itself to the real electrolytic nature of the amino acids by seeing them as RCH(NH2)COOH rather than RCH(NH3+)COO- greatly handicaps exploitation of this advantage). These features undoubtedly underlie their biologicalimportancetoo, butthey havemadepertinent,toawiderangeofotherorganic molecules,thebiologicalmeans by whichtheirtransmembraneflowsaredeterminedand expressed. This range includes various other metabolites,hormones, small peptides and their analogs, drugs, and other environmental factors. The relationship of their transmembrane flows to linked movements of inorganic ions speaks also to the fundamental breadth of our subject. . Thisseriesof reviews will be found to progress through thissuccession ofcentral interests. At least some of these chapters will be seen quite appropriately to reflect directly on the phenomenon of membrane transport for itsown sake,a subject that still needs finishing while we reach forward to try to understand the whole pattern of the flows of metabolism. Furthermore, as the possibility emerges of identifying and characterizing the proteins catalyzing and regulating these events, the importance of accurately characterizingeach participating membrane transport system increases. But for this aspectalso,the biologyof membrane transport has moved far beyond the naked concept of permeability and its interruption, once supposed to occur solely by enzyme v action, or to be mediated by lipids, or to be energized in isolation from other cellular energy transduction. Instead it has grown to be tightly associated with almost all other metabolic events. Oneshouldnot introduceourtitlesubjectwithoutattemptingtoconstructabridge crossingthe interveningchaptersto the concludingessay entitledInterorganAminoAcid Nutrition, which I have the privilegealso to offer. It isan admitted bias to regard that subject as our principal and ultimate target: how are the flows of the amino acids and their metabolites, along with the linked flows of inorganic ions, all ultimately to be integrated intotheir places,to understand the overall flows of biological function? The concept of that overall flow of metabolism led Peter Mitchell to a striking, if perhaps slightlyexaggerateddictum:"itiseasiertounderstandbiochemistryin termsoftransport, than it is to understand transport in terms of biochemistry." Recent work suggests that transport receptor sites may have proved attractive for secondary exploitations as cell surface receptors for viruses. Thus, perhaps allowing viral infections to contribute as they do to nutritional problems, and transport abnormalities to influence viral pathogenesis (Kim sa lll., 1991; Wang sa lll., 1991). Will the discrimination between transporters per se from associated transport regulators present further problems? How far will the emergingtendencyof transport mediators toformproteinsuperfamilies go? (Gibson et aI., 1991). As James H. Schwartz remarks, "the amount of functional information the can be derived from protein structure is astonishing." The participating authors have sought to review the subject broadly, rather than to limit attention to studies made in a particular laboratory. We depend, however, on each authorship for sensitivity to the personal knowledge growing out of that area of participation, and we are also aware that some of the subjects are so new that the corresponding chapters arise for the moment from rather few labs. REFERENCES Gibson, A.L., Wagner, L.M.,Collins, F.S.and Oxender, D.L., 1991,Science 254:109. Kim,J.W.,Closs, E.I., Albritton, L.M.and Cunningham, J.M., 1991,Nature 352:725. Van Slyke, D.D.and Meyer, G.M., 1913, J.BioI.Chern. 16:197. Wang, H., Kavanaugh, M.P.,North, R.A.and Kabat, D., 1991, Nature 352:728. H.N. Christensen vi PREFACE Transport of amino acids or their derivatives across biological membranes is a highly controlled process. Nature has evolved more or less specific transport systems whichallowaminoacid transfer betweendifferentsubcellularcompartmentson the one hand and between the cellular interior and its extracellular environment on the other. However,it would bean oversimplificationtoview the role ofaminoacid transportonly as asubstratetranslocation from one sideofa membrane to the other. Forexample,flux through many amino acid-metabolizing pathways is controlled by transmembrane and interorgan amino acid transport,rendering transportas an importantsite for control of aminoacid metabolism. More recently,it has becomeclear thatenergy-dependentamino acid transporters can build up osmotic gradients across the plasma membrane,resulting in alterationsofcellular volumeand cellularfunction,such as protein turnover and cell growth. Thus, amino acid transport also must receive attention in terms of inter-and intracellular signalling. Recent advances in knowledge are presented here in an indepth treatment by experts in this active research area from the viewpoint of physiology, biochemistry, molecular biology and medicine. This includes the methodological aspects for assessing amino acid transport systems, their energetics, the specific features of amino acid transportin differentsubcellularorganellesandtissues,thefunctionalconsequencesand physiological importance, ontogenetic aspects, as well as intercellular and interorgan transport. Thus, the book is not only of interest to biochemists, physiologists, and cell biologists, but also for the interested student and physician. Finally,it isa pleasuretothank the manycolleagueswho havecontributed to this project by giving their advice and critique. We are especially thankful to Dr. H.N. Christensen for overtaking the task to summarize the recent advances in physiological interorgan flows of the amino acids. His professional life has been dedicated to the subject of amino acid transport and his contributions to the field are innumerable. We also are indebted toMs.Maria Chan for preparing the layoutof the book and for help in compiling the entries to the subject index, and to our secretaries Ms. Vanessa Garrison and Ms. Petra Ochsenfarth for their patient efforts on our behalf. Wehope that this extensive and integrating account of present knowledge will provide a useful platform for further research in this field. February 1992 DieterHaussinger Michael Kilberg vii CONTENTS PART A: GENERAL ASPECTS Amino Acid Transporters: Systematic Approach and Principles of ControL.................................................................................................... 3 G.G.Guidotti and G.C.Gazzola Energetics of Amino Acid Transport................................................................................ 31 A.A.Eddy Techniques Used in the Study of Plasma Membrane Amino Acid Transport................................................................................................... 51 J.D.McGivan Molecular Biological Approaches for Amino Acid Transport............................... 65 R.M.Williamson, T.Z.Su and D.L.Oxender Amino Acid Transport During Embryogenesis............................................................ 75 L.J.Van Winkle Amino Acid Transport by Lysosomes................................................................................ 89 R.L.Pisoni and J.A.Schneider Amino Acid Transport in Mitochondria.......................................................................... 101 J.D. McGivan Amino Acid Transport,Cell Volume and Regulation of Cell Growth................................................................................................................... 113 D.Haussinger, F. Lang and M.S. Kilberg PART B: TISSUE SPECIFIC TRANSPORT AND FUNCTIONAL IMPLICATIONS Amino Acid Transport in Liver........................................................................................... 133 M.S.Kilberg and D.Haussinger Amino Acid Transport in Intestine.................................................................................... 149 B.R.Stevens Amino Acid Transport in Brain........................................................................................... 165 Q.R.Smith and A.J.L.Cooper Muscle Amino Acid Metabolism and Transport........................................................... 195 B.Mackenzie, A.Ahmed and M.J.Rennie ix Amino Acid Transport in the Kidney............................................................................... 233 J.S.Schwegler, S.Sibernagl, B.K.Tamarappoo and T.C.WeIbourne Amino Acid Transport in Lymphocytes........................................................................... 261 G.B.Segel Transport of Cysteinyl Leukotrienes................................................................................ 275 D.Keppler, M.Maller and T.Ishikawa Interorgan Glutathione Transport...................................................................................... 283 T.P.M.Akerboom and H. Sies Interorgan Amino Acid Nutrition...................................................................................... 295 H.N. Christensen INDEX............................................................................................................................................. 305 x PART A GENERAL ASPECTS