Abstract
Glutamatergic neurotransmission entails a tonic loss of glutamate from nerve endings into the synapse. Replacement of neuronal glutamate is essential in order to avoid depletion of the internal pool. In brain this occurs primarily via the glutamate-glutamine cycle, which invokes astrocytic synthesis of glutamine and hydrolysis of this amino acid via neuronal phosphate-dependent glutaminase. This cycle maintains constancy of internal pools, but it does not provide a mechanism for inevitable losses of glutamate N from brain. Import of glutamine or glutamate from blood does not occur to any appreciable extent. However, the branched-chain amino acids (BCAA) cross the blood–brain barrier swiftly. The brain possesses abundant branched-chain amino acid transaminase activity which replenishes brain glutamate and also generates branched-chain ketoacids. It seems probable that the branched-chain amino acids and ketoacids participate in a “glutamate-BCAA cycle” which involves shuttling of branched-chain amino acids and ketoacids between astrocytes and neurons. This mechanism not only supports the synthesis of glutamate, it also may constitute a mechanism by which high (and potentially toxic) concentrations of glutamate can be avoided by the re-amination of branched-chain ketoacids.
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Abbott NJ, Rönnbäck L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7(1):41–53
Albrecht J, Sonnewald U, Waagepetersen HS, Schousboe A (2007) Glutamine in the central nervous system: function and dysfunction. Front Biosci 12:332–343
Auestad N, Korsak RA, Morrow JW, Edmond J (1991) Fatty acid oxidation and ketogenesis by astrocytes in primary culture. J Neurochem 56:1376–1386
Bak LK, Johansen ML, Schousboe A, Waagepetersen (2012) Valine but not leucine or isoleucine supports neurotransmitter glutamate synthesis during synaptic activity in cultured cerebellar neurons. J Neurosci Res 90:1768–1775
Bak LK, Waagepetersen HS, Sørensen M, Ott P, Vilstrup H, Keiding S, Schousboe A (2013) Role of branched chain amino acids in cerebral ammonia homeostasis related to hepatic encephalopathy. Metab Brain Disabil 28:209–215
Berl S, Takagaki G, Clarke DD, Waelsch H (1962) Metabolic compartments in vivo. Ammonia and glutamic acid metabolism in brain and liver. J BiolChem 237:2562–2569
Bixel MG, Hamprecht B (1994) Metabolism of branched-chain amino acids in astroglial-rich primary culture. J Neurochem 63:S62A
Bixel M, Hutson S, Hamprecht B (1997) Cellular distribution of branched chain amino acid aminotransferase isoenzymes among rat brain glial cells in culture. J Histochem Cytochem 45:685–694
Boneh A (2015) Signal transduction in inherited metabolic disorders: a model for a possible pathogenetic mechanism. J Inherit Metab Disabil 38:729–740
Bonfils J, Faure M, Gibrat JF, Glomot F, Papet I (2000) Sheep cytosolic branched-chain amino acid aminotransferase: cDNA cloning, primary structure and molecular modelling and its unique expression in muscles. Biochim Biophys Acta 1494:129–136
Brand K (1981) Metabolism of 2-oxoacid analogues of leucine, valine and phenylalanine by heart muscle, brain and kidney of the rat. Biochim Biophys Acta 677:126–132
Brightman MW, Cheng-Tao J-H (1988) Cell membrane interactions between astrocytes and brain endothelium. In: Norenberg MD, Hertz L, Schousboe A (eds) The biochemical pathology of astrocytes. Alan R. Liss, Inc., New York, pp 21–39
Broer S, Broer A, Hamprecht B (1994) Expression of Na+-independent isoleucine transport activity from rat brain in Xenopus laevis oocytes. Biochim Biophys Acta 1192:95–100
Brookes N (1992) Effect of intracellular glutamine on the uptake of large neutral amino acids in astrocyes: concentrative Na(+)-independent transport. J Neurochem 59:227–235
Brookes N (1993) Interaction between the glutamine cycle and the uptake of large neutral amino acids in astrocytes. J Neurochem 60:1923–1928
Burch HB, Cambon N, Lowry OH (1985) Branched-chain amino acid aminotransferase along the rabbit and rat nephron. Kidney Int 28:114–117
Burrage LC, Nagamani SC, Campeau PM, Lee BH (2014) Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders. Hum Mol Genet 23:R1–R8
Cangiano C, Cardelli-Cangiano P, James J, Rossi Fanelli F, Patrizi MA, Brackett KA, Strom R, Fischer JE (1983) Brain microvessels take up large neutral amino acids in exchange for glutamine. J Biol Chem 258:8949–8954
Cardona C, Sánchez-Mejías E, Dávila JC, Martín-Rufián M, Campos-Sandoval JA, Vitorica J, Alonso FJ, Matés JM, Segura JA, Norenberg MD, Rama Rao KV, Jayakumar AR, Gutiérrez A, Márquez J (2015) Expression of Gls and Gls2 glutaminase isoforms in astrocytes. Glia 63:365–382
Chaplin ER, Goldberg AL, Diamond I (1976) Leucine oxidation in brain slices and nerve endings. J Neurochem 26:701–707
Choi S, Disilvio B, Fernstrom MH, Fernstrom JD (2013) Oral branched-chain amino acid supplements that reduce brain serotonin during exercise in rats also lower brain catecholamines. Amino Acids 45:1133–1142
Cole JT, Mitala CM, Kundu S, Verma A, Elkind JA, Nissim I, Cohen AS (2010) Dietary branched chain amino acids ameliorate injury-induced cognitive impairment. Proc Natl Acad Sci USA 107:366–371
Cooper AJL, McDonald JM, Gelbard AS, Gledhill RF, Duffy TE (1979) The metabolic fate of 13N-labelled ammonia in rat brain. J Biol Chem 254:4982–4992
Cooper AJL, Jeitner TM (2016) Central role of glutamate metabolism in the maintenance of nitrogen homeostasis in normal and hyperammonemic brain. Biomolecules. doi:10.3390/biom6020016
Curtis DR, Watkins JC (1960) The excitation and depression of spinal neurones by structurally related amino acids. J Neurochem 6:117–141
Daikhin Y, Yudkoff M (2000) Compartmentation of brain glutamate metabolism in neurons and glia. J Nutr 130:1026S–1031S
Dam G, Ott P, Aagaard NK, Vilstrup H (2013) Branched-chain amino acids and muscle ammonia detoxification in cirrhosis. Metab Brain Disabil 28:217–220
Davoodi J, Drown PM, Bledsoe RK, Wallin R, Reinhart GD, Hutson SM (1998) Overexpression and characterisation of the human mitochondrial and cytosolic branched-chain aminotransferases. J Biol Chem 273:4982–4989
Dienel GA (2012) Brain lactate metabolism: the discoveries and the controversies. J Cereb Blood Flow Metab 32:1107–1138
Dodd PR, Williams SH, Gundlach AL, Harper PA, Healy PJ, Dennis JA, Johnston GA (1992) Glutamate and gamma-aminobutyric acid neurotransmitter systems in the acute phase of maple syrup urine disease and citrullinemia encephalopathies in newborn calves. J Neurochem 59:582–590
Drgonova J, Jacobsson JA, Han JC, Yanovski JA, Fredriksson R, Marcus C, Schiöth HB, Uhl GR (2013) Involvement of the neutral amino acid transporter SLC6A15 and leucine in obesity-related phenotypes. PLoS One 8:e68245. doi:10.1371/journal.pone.0068245
Erecinska M, Nelson D, Wilson DF, Silver IA (1984) Neurotransmitter amino acids in the CNS. I. Regional changes in amino acid levels in rat brain during ischemia and reperfusion. Brain Res 304:9–22
Erecińska M, Nelson D, Daikhin Y, Yudkoff M (1996) Regulation of GABA level in rat brain synaptosomes: fluxes through enzymes of the GABA shunt and effects of glutamate, calcium, and ketone bodies. J Neurochem 67:2325–2334
Evangeliou A, Spilioti M, Doulioglou V, Kalaidopoulou P, Ilias A, Skarpalezou A, Katsanika I, Kalamitsou S, Vasilaki K, Chatziioanidis I, Garganis K, Pavlou E, Varlamis S, Nikolaidis N (2009) Branched chain amino acids as adjunctive therapy to ketogenic diet in epilepsy: pilot study and hypothesis. J Child Neurol 24:1268–1272
Felig P (1975) Amino acid metabolism in man. Annu Rev Biochem 44:933–955
García-Espinosa MA, Wallin R, Hutson SM, Sweatt AJ (2007) Widespread neuronal expression of branched-chain aminotransferase in the CNS: implications for leucine/glutamate metabolism and for signaling by amino acids. J Neurochem 100:1458–1468
Gluud LL, Dam G, Borre M, Les I, Cordoba J, Marchesini G, Aagaard NK, Risum N, Vilstrup H (2013) Oral branched-chain amino acids have a beneficial effect on manifestations of hepatic encephalopathy in a systematic review with meta-analyses of randomized controlled trials. J Nutr 143:1263–1268
Grill V, Björkhem M, Gutniak M, Lindqvist M (1992) Brain uptake and release of amino acids in nondiabetic and insulin-dependent diabetic subjects: important role of glutamine release for nitrogen balance. Metabolism 41:28–32
Hädel S, Wirth C, Rapp M, Gallinat J, Schubert F (2013) Effects of age and sex on the concentrations of glutamate and glutamine in the human brain. J Magn Res Imaging 38:1480–1487
Hall TR, Wallin R, Reinhart GD, Hutson SM (1993) Branched chain aminotransferase isoenzymes. Purification and characterization of the rat brain isoenzyme. J Biol Chem 268:3092–3098
Hamprecht B, Schmoll D, Cesar M, Bixel B, Vogel R, Kurz G, Wiesinger H (1995) Metabolism of glucogenic and ketogenic amino acids and energy metabolism in astroglial cells. J Neurochem 64:S110A
Harper AE, Miller RH, Block KP (1984) Branched-chain amino acid metabolism. Ann Rev Nutr 4:409–454
Harris RA, Kobayashi R, Murakami T, Shimomura Y (2001) Regulation of branched-chain alpha-keto acid dehydrogenase kinase expression in rat liver. J Nutr 131:841S–845S
Hayashi T (1952) A physiological study of epileptic seizures following cortical stimulation in animals and its application to human clinics. Jpn J Physiol 3:46–64
Haymond MW, Ben-Galim E, Strobel KE (1978) Glucose and alanine metabolism in children with maple syrup urine disease. J Clin Invest 78:398–405
Hull J, Hindy ME, Kehoe PG, Chalmers K, Love S, Conway ME (2012) Distribution of the branched chain aminotransferase proteins in the human brain and their role in glutamate regulation. J Neurochem 123:997–1009
Hutson SM (1988) Subcellular distribution of branched-chain aminotransferase activity in rat tissues. J Nutr 118:1475–1481
Hutson SM, Wallin R, Hall TR (1992) Identification of mitochondrial branched chain aminotransferase and its isoforms in rat tissues. J Biol Chem 267:15681–15686
Hutson SM, Berkich D, Drown P, Xu B, Aschner M, LaNoue KF (1998) Role of branched-chain aminotransferase isoenzymes and gabapentin in neurotransmitter metabolism. J Neurochem 71:863–874
Hutson SM, Lieth E, LaNoue KF (2001) Function of leucine in excitatory neurotransmitter metabolism in the central nervous system. J Nutr 131:846S–850S
James JH, Escourrou J, Fischer JE (1978) Blood brain neutral amino acid transport activity is increased after portacaval anastomosis. Science 200(1395):1397
Jan W, Zimmerman RA, Wang ZJ, Berry GT, Kaplan PB, Kaye EM (2003) MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation. Neuroradiology 45:393–399
Jenstad M, Chaudhry FA (2013) The amino acid transporters of the glutamate/GABA-glutamine cycle and their impact on insulin and glucagon secretion. Front Endocrinol. doi:10.3389/fendo.2013.00199
Jewell JL, Russell RC, Guan KL (2013) Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol 14:133–139
Kanamori K, Ross BD, Kondrat RW (1998) Rate of glutamate synthesis from leucine in rat brain measured in vivo by 15N NMR. J Neurochem 70(3):1304–1315
Kvamme E, Svenneby G, Hertz L, Schousboe A (1982) Properties of phosphate activated glutaminase in astrocytes cultured from mouse brain. Neurochem Res 7:761–770
Lee WJ, Hawkins RA, Viña JR, Peterson DR (1998) Glutamine transport by the blood–brain barrier: a possible mechanism for nitrogen removal. Am J Physiol 274:C1101–C1107
Li F, Yin Y, Tan B, Kong X, Wu G (2011) Leucine nutrition in animals and humans: mTOR signaling and beyond. Amino Acids 41:1185–1193
Lieth E, LaNoue KF, Berkich DA, Xu B, Ratz M, Taylor C, Hutson SM (2001) Nitrogen shuttling between neurons and glial cells during glutamate synthesis. J Neurochem 76:1712–1723
Llorente-Folch I, Rueda CB, Amigo I, del Arco A, Saheki T, Pardo B, Satrústegui J (2013) Calcium-regulation of mitochondrial respiration maintains ATP homeostasis and requires ARALAR/AGC1-malate aspartate shuttle in intact cortical neurons. J Neurosci 33:13957–13971
Mac M, Nehlig A, Nałecz MJ, Nałecz KA (2000) Transport of alpha-ketoisocaproate in rat cerebral cortical neurons. Arch Biochem Biophys 376:347–353
Manchester KL (1965) Oxidation of amino acids by isolated rat diaphragm and the influence of insulin. Biochim Biophys Acta 100:295–298
Martinez-Hernandez A, Bell KP, Norenberg MD (1977) Glutamine synthetase: glial localization in brain. Science 195:1356–1358
McKenna MC (1996) Introduction: metabolic trafficking comes of age in the decade of the brain. Dev Neurosci 18:333–335
McKenna MC (2007) The glutamate-glutamine cycle is not stoichiometric: fates of glutamate in brain. J Neurosci Res 85:3347–3358
McKenna MC, Tildon JT, Stevenson JH, Boatright R, Huang S. (1993) Regulation of energy metabolism in synaptic terminals and cultured rat brain astrocytes: differences revealed using aminooxyacetate. Dev Neurosci 15:320–329
Meldrum BS (2000) Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr 130:1007S–1015S
Miller LL (1961) The role of the liver and nonhepatic tissue in the regulation of free amino acid levels in the blood. In: Holden JT (ed) Amino acid pools. Elsevier, Amsterdam, pp 708–721
Muelly ER, Moore GJ, Bunce SC, Mack J, Bigler DC, Morton DH, Strauss KA (2013) Biochemical correlates of neuropsychiatric illness in maple syrup urine disease. J Clin Invest 123:1809–1820
Murín R, Hamprecht B (2008) Metabolic and regulatory roles of leucine in neural cells. Neurochem Res 33:279–284
Newsholme EA, Blomstrand E (2006) Branched-chain amino acids and central fatigue. J Nutr 136:274S–276S
Norenberg MD, Martinez-Hernandez A (1979) Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res 161:303–310
Oldendorf WH (1971) Brain uptake of radiolabeled amino acids, amines and hexoses after arterial injection. Am J Physiol 221:1629–1635
Petzold GC, Murthy VN (2011) Role of astrocytes in neurovascular coupling. Neuron 71:782–797
Prensky AL, Moser HW (1966) Brain lipids, proteolipids, and free amino acids in maple syrup urine disease. J Neurochem 13:863–874
Rao KVR, Murthy CRK (1994) High affinity transport systems for essential amino acids in rat brain cortex. Neurosci Lett 175:103–106
Rao KVR, Vemuri MC, Murthy CRK (1995) Synaptosomal transport of branched chain amino acids in young, adult and aged rat brain cortex. Neurosci Lett 184:137–140
Riviello JJ Jr, Rezvani I et al (1991) Cerebral edema causing death in children with maple syrup urine disease. J Pediatr 119:42–45
Robinson MB, Jackson JG (2016) Astroglial glutamate transporters coordinate excitatory signaling and brain energetics. Neurochem Int 98:56–71
Rothman DL, DeFeyter HM, Maciejewski PK, Behar KL (2012) Is there in vivo evidence for amino acid shuttles carrying ammonia from neurons to astrocytes?. Neurochem Res 37:2597–2612
Schwartz GJ (2013) Central leucine sensing in the control of energy homeostasis. Endocrinol Metab Clin North Am 42:81–87
Shambaugh GE III, Koehler RA (1981) Fetal fuels. IV. Regulation of branched-chain amino and keto acid metabolism in fetal brain. Am J Physiol 241:E200–E207
Shambaugh GE, Koehler RA (1983) Fetal fuels VI. Metabolism of a-ketoisocaproic acid in fetal rat brain. Metabolism 32:421–427
Shen J (2013) Modeling the glutamate–glutamine neurotransmitter cycle. Front Neuroenerget 5:1. doi:10.3389/fnene.2013.00001 (eCollection 2013)
Shulman RG, Hyder F, Rothman DL (2001) Lactate efflux and the neuroenergetic basis of brain function. NMR Biomed 14:389–396
Siesjö BK (1978) Brain energy metabolism. Wiley, New York
Smith QR, Momma S, Aoyagi M, Rapoport SI (1987) Kinetics of neutral amino acid transport across the blood-brain barrier. J Neurochem 49:1651–1658
Snell K, Duff DA (1981) In: Walser M, Williamson JR (eds) Metabolism and clinical implications of branched chain amino and ketoacids. Elsevier/North-Holland, New York, pp 251–256
Sonnewald U (2014) Glutamate synthesis has to be matched by its degradation-where do all the carbons go?. J Neurochem 131:399–406
Sweatt A, Garcia-Espinosa M, Wallin R, Hutson S (2004a) Branched-chain amino acids and neurotransmitter metabolism: expression of cytosolic brainched chain aminotransferase (BCATc) in the cerebellum and hippocampus. J Compar Neurol 477:360–370
Sweatt A, Wood M, Suryawan A, Wallin R, Willingham M, Hutson S (2004b) Branched-chain amino acid catabolism: unique segregation of pathway enzymes in organ systems and peripheral nerves. Am J Phys Endocr Metab 286:E64–E76
Tan CH, Leong MK, Ng FH, Thiyagarajah P (1987) Sodium-independent synaptosomal uptake of leucine. Biochem Int 14:161–166
Tan CH, Leong MK, Ng FG (1988) A novel sodium-dependent uptake system for L-leucine in rat brain synaptosomes. Neurochem Int 12:91–95
Westergaard N, Sonnewald U, Schousboe A (1995) Metabolic trafficking between neurons and astrocytes: the glutamate/glutamine cycle revisited. Dev Neurosci 17:203–211
Walls AB, Waagepetersen HS, Bak LK, Schousboe A, Sonnewald U (2015) The glutamine-glutamate/GABA cycle: function, regional differences in glutamate and GABA production and effects of interference with GABA metabolism. Neurochem Res 40(2):402–409
Yudkoff M, Nissim I, Kim SU, Pleasure D, Hummeler K, Segal S (1983) [15N] Leucine as a source of [15N] glutamate in organotypic cerebellar explants. Biochem Biophys Res Commun 115:l74–l79
Yudkoff M, Nissim I, Hertz L (1990) Precursors of glutamic acid nitrogen in primary neuronal cultures: studies with 15N. Neurochem Res 15:1191–1196
Yudkoff M, Daikhin Y, Lin Z-P, Nissim I, Stern J, Pleasure D, Nissim I (1994a) Inter-relationships of leucine and glutamate metabolism in cultured astrocytes. J Neurochem 62:1192–1202
Yudkoff M, Daikhin Y, Nelson D, Nissim I, Erecińska M (1996) Neuronal metabolism of branched-chain amino acids: flux through the aminotransferase pathway in synaptosomes. J Neurochem 66:2136–2145
Yudkoff M, Daikhin Y, Nissim I, Horyn O, Luhovyy B, Lazarow A, Nissim I (2005) Brain amino acid requirements and toxicity: the example of leucine. J Nutr 135:1531S–1538S
Zielke HR, Tildon JT, Zielke CL, Baab PJ, Landry ME (1989) Functional intracellular glutaminase activity in intact astrocytes. Neurochem Res 14:327–332
Zielke HR, Huang Y, Zielke CL, Baab PJ, Tildon JT (1995) a-Ketoisocaproate and leucine infusion into the brain alters the amino acid levels in the interstitital space. J Neurochem 64:S56A
Zielke HR, Huang Y, Baab PJ, Collins RM Jr, Zielke CL, Tildon JT (1998) Effect of alpha-ketoisocaproate and leucine on the in vivo oxidation of glutamate and glutamine in the rat brain. Neurochem Res 22:1159–1164
Zinnanti WJ, Lazovic J (2012) Interrupting the mechanisms of brain injury in a model of maple syrup urine disease encephalopathy. J Inherit Metab Dis 35:71–79
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Yudkoff, M. Interactions in the Metabolism of Glutamate and the Branched-Chain Amino Acids and Ketoacids in the CNS. Neurochem Res 42, 10–18 (2017). https://doi.org/10.1007/s11064-016-2057-z
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DOI: https://doi.org/10.1007/s11064-016-2057-z