Abstract
l-Theanine (=γ-glutamylethylamide) is an amino acid ingredient in green tea with a structural analogy to l-glutamine (l-GLN) rather than l-glutamic acid (l-GLU), with regards to the absence of a free carboxylic acid moiety from the gamma carbon position. l-theanine markedly inhibits [3H]l-GLN uptake without affecting [3H]l-GLU uptake in cultured neurons and astroglia. In neural progenitor cells with sustained exposure to l-theanine, upregulation of the l-GLN transporter isoform Slc38a1 expression and promotion of both proliferation and neuronal commitment are seen along with marked acceleration of the phosphorylation of mammalian target of rapamycin (mTOR) and relevant downstream proteins. Stable overexpression of Slc38a1 leads to promotion of cellular growth with facilitated neuronal commitment in pluripotent embryonic carcinoma P19 cells. In P19 cells stably overexpressing Slc38a1, marked phosphorylation is seen with mTOR and downstream proteins in a fashion insensitive to the additional stimulation by l-theanine. The green tea amino acid l-theanine could thus elicit pharmacological actions to up-regulate Slc38a1 expression for activation of the mTOR signaling pathway required for cell growth together with accelerated neurogenesis after sustained exposure in undifferentiated neural progenitor cells. In this review, I summarize a novel pharmacological property of the green tea amino acid l-theanine for embryonic and adult neurogenesis with a focus on the endogenous amino acid analog l-GLN. A possible translational strategy is also discussed on the development of dietary supplements and nutraceuticals enriched of l-theanine for the prophylaxis of a variety of untoward impairments and malfunctions seen in patients with different neurodegenerative and/or neuropsychiatric disorders.
Similar content being viewed by others
Abbreviations
- ADHD:
-
Attention deficit hyperactivity disorder
- AP1:
-
Activator protein-1
- bHLH:
-
Basic helix-loop-helix
- BrdU:
-
5-bromo-2′-deoxyuridine
- CREB:
-
Cyclic AMP responsive element binding protein
- DG:
-
Dentate gyrus
- EAA:
-
Essential amino acids
- ER:
-
Endoplasmic reticulum
- GABA:
-
γ-aminobutyric acid
- GFAP:
-
Glial fibrillary acidic protein
- GFP:
-
Green fluorescent protein
- GLN:
-
Glutamine
- GlnT:
-
GLN transporter
- GLU:
-
Glutamic acid
- MAP2:
-
Microtubule-associated protein-2
- MeAIB:
-
N-methylaminoisobutyric acid
- mTOR:
-
Mammalian target of rapamycin
- MTT:
-
3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide
- NSCs:
-
Neural stem cells
- Slc38a1:
-
Solute carrier 38a1
- XBP1:
-
X-box binding protein-1
References
Kakuda T, Hinoi E, Abe A, Nozawa A, Ogura M, Yoneda Y (2008) L-theanine, an ingredient of green tea, inhibits [3H]GLN transport in neurons and astroglia in rat brain. J Neurosci Res 86:1846–1856
Szatkowski M, Attwell D (1994) Triggering and execution of neuronal death in brain ischemia: two phases of glutamate release by different mechanisms. Trends Neurosci 17:359–365
Schousboe A, Hertz L, Svenneby G, Kvamme E (1979) Phosphate activated glutaminase activity and GLN uptake in primary cultures of astrocytes. J Neurochem 32:943–950
Di X, Yan J, Zhao Y, Zhang J, Shi Z, Chang Y, Zhao B (2000) L-L-theanine protects the APP (Swedish mutation) transgenic SH-SY5Y cell against glutamate-induced excitotoxicity via inhibition of the NMDA receptor pathway. Neuroscience 168:778–786
Ota M, Wakabayashi C, Sato N, Hori H, Hattori K, Teraishi T, Ozawa H, Okubo T, Kunugi H (2015) Effect of L-L-theanine on glutamatergic function in patients with schizophrenia. Acta Neuropsychiatr 27:291–296
Goto T, Yoshida Y, Amano I, Horie H (1996) Chemical composition of commercially available Japanese green tea. Foods Food Ingred J 170:46–51
Yokogoshi H, Kobayashi M, Mochizuki M, Terashima T (1998) Effect of L-theanine, γ-glutamylethylamide, on brain monoamines and striatal dopamine release in conscious rats. Neurochem Res 23:667–673
Kakuda T, Nozawa A, Unno T, Okamura N, Okai O (2000) Inhibiting effects of L-theanine on caffeine stimulation evaluated by EEG in the rat. Biosci Biotechnol Biochem 64:287–293
Yokogoshi H, Kato Y, Sagesaka YM, Takihara-Matsuura T, Kakuda T, Takeuchi N (1995) Reduction effect of L-theanine on blood pressure and brain 5-hydroxyindoles in spontaneously hypertensive rats. Biosci Biotechnol Biochem 59:615–618
Kakuda T, Yanase H, Utsunomiya K, Nozawa A, Unno T, Kataoka K (2000) Protective effect of γ-glutamylethylamide (L-theanine) on ischemic delayed neuronal death in gerbils. Neurosci Lett 289:189–192
Kakuda T, Nozawa A, Sugimoto A, Niino H (2002) Inhibition by L-theanine of binding of [3H]AMPA, [3H]kainate, and [3H]MDL 105,519 to glutamate receptors. Biosci Biotechnol Biochem 66:2683–2686
Frandsen A, Schousboe A (1993) Excitatory amino acid-mediated cytotoxicity and calcium homeostasis in cultured neurons. J Neurochem 60:1202–1211
Kimura K, Ozeki M, Juneja LR, Ohira H (2007) L-L-theanine reduces psychological and physiological stress response. Biol Psychol 74:39–45
Yoto A, Motoki M, Murano S, Yokogoshi H (2012) Effects of L-L-theanine or caffeine intake on changes in blood pressure under physical and psychological stresses. J Physiol Anthropol 31:28
Hidese S, Ota M, Wakabayashi C, Noda T, Ozawa H, Okubo T, Kunugi H (2016) Effects of chronic l-L-theanine administration in patients with major depressive disorder: an open label study. Acta Neuropsychiatr 11:1–8
Lyon MR, Kapoor MP, Juneja LR (2011) The effects of L-L-theanine (SunL-theanine) on objective sleep quality in boys with attention deficit hyperactivity disorder (ADHD): a randomized, double-blind, placebo-controlled clinical trial. Altern Med Rev 16:348–354
Barrett JR, Tracy DK, Giaroli G (2013) To sleep or not sleep: a systemic review of the literature of pharmacological treatments of insomnia in children and adolescents with attention deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 23:640–647
Rao TP, Ozeki M, Juneja LR (2015) In search of a safe natural sleep aid. J Am Coll Nutr 34:436–447
Balcar VJ, Johnston GAR (1975) High affinity uptake of L-GLN in rat brain slices. J Neurochem 24:875–879
Reimer RJ, Chaudhry FA, Gray AT, Edwards RH (2000) Amino acid transport system A resembles system N in sequence but differs in mechanism. Proc Natl Acad Sci USA 97:7715–7720
Sugawara M, Nakanishi T, Fei YJ, Huang W, Ganapathy ME, Leibach FH, Ganapathy V (2000) Cloning of an amino acid transporter with functional characteristics and tissue expression pattern identical to that of system A. J Biol Chem 275:16473–16477
Varoqui H, Zhu H, Yao D, Ming H, Erickson JD (2000) Cloning and functional identification of a neuronal GLN transporter. J Biol Chem 275:4049–4054
Broer A, Brookes N, Ganapathy V, Dimmer KS, Wagner CA, Lang F, Broer S (1999) The astroglial ASCT2 amino acid transporter as a mediator of GLN efflux. J Neurochem 73:2184–2194
Utsunomiya-Tate N, Endou H, Kanai Y (1996) Cloning and functional characterization of a system ASC-like Na+-dependent neutral amino acid transporter. J Biol Chem 271:14883–14890
Broer A, Albers A, Setiawan I, Edwards RH, Chaudhry FA, Lang F, Wagner CA, Broer S (2002) Regulation of the GLN transporter SN1 by extracellular pH and intracellular sodium ions. J Physiol 539:3–14
Chaudhry FA, Reimer RJ, Krizaj D, Barber D, Storm-Mathisen J, Copenhagen DR, Edwards RH (1999) Molecular analysis of system N suggests novel physiological roles in nitrogen metabolism and synaptic transmission. Cell 99:769–780
Chillaron J, Roca R, Valencia A, Zorzano A, Palacn M (2001) Heteromeric amino acid transporters: biochemistry, genetics, and physiology. Am J Physiol Renal Physiol 281:F995–F1018
Wagner CA, Lang F, Broer S (2001) Function and structure of heteromeric amino acid transporters. Am J Physiol Cell Physiol 281:C1077–C1093
Broer S (2002) Adaptation of plasma membrane amino acid transport mechanisms to physiological demands. Pflugers Arch 444:457–466
Nagaraja TN, Brookes N (1996) GLN transport in mouse cerebral astrocytes. J Neurochem 66:1665–1674
Albers A, Broer A, Wagner CA, Setiawan I, Lang PA, Kranz EU, Lang F, Broer S (2001) Na+ transport by the neural GLN transporter ATA1. Pflugers Arch 443:92–101
Chaudhry FA, Schmitz D, Reimer RJ, Larsson P, Gray AT, Nicoll R, Kavanaugh M, Edwards RH (2002) GLN uptake by neurons: interaction of protons with system a transporters. J Neurosci 22:62–72
Dolinska M, Zablocka B, Sonnewald U, Albrecht J (2004) GLN uptake and expression of mRNA’s of GLN transporting proteins in mouse cerebellar and cerebral cortical astrocytes and neurons. Neurochem Int 44:75–81
Tsuge H, Sano S, Hayakawa T, Kakuda T, Unno T (2003) L-theanine, gamma-glutamylethylamide, is metabolized by renal phosphate-independent glutaminase. Biochim Biophys Acta 1620:47–53
D’Aniello A, Fisher G, Migliaccio N, Cammisa G, D’Aniello E, Spinelli P (2005) Amino acids and transaminases activity in ventricular CSF and in brain of normal and Alzheimer patients. Neurosci Lett 388:49–53
Mackenzie B, Schafer MKH, Erickson JD, Hediger MA, Weihe E, Varoqui H (2003) Functional properties and cellular distribution of the system A GLN transporter SNAT1 support specialized roles in central neurons. J Biol Chem 278:23720–23730
Christensen HN (1990) Role of amino acid transport and countertransport in nutrition and metabolism. Physiol Rev 70:3–77
McGivan J, Pastor-Anglada M (1994) Regulatory and molecular aspects of mammalian amino acid transport. Biochem J 299:321–334
Heckel T, Broer A, Wiesinger H, Lang F, Broer S (2003) Asymmetry of GLN transporters in cultured neural cells. Neurochem Int 43:289–298
Deitmer JW, Broer A, Broer S (2003) GLN efflux from astrocytes is mediated by multiple pathways. J Neurochem 87:127–135
Melone M, Quagliano F, Barbaresi P, Varoqui H, Erickson JD, Conti F (2004) Localization of the GLN transporter SNAT1 in rat cerebral cortex and neighboring structures, with a note on its localization in human cortex. Cereb Cortex 14:562–574
Ogura M, Nakamichi N, Takano K, Oikawa H, Kambe Y, Ohno Y, Taniura H, Yoneda Y (2006) Functional expression of a GLN transporter responsive to down-regulation by lipopolysaccharide through reduced promoter activity in cultured rat neocortical astrocytes. J Neurosci Res 83:1447–1460
Ogura M, Taniura H, Nakamichi N, Yoneda Y (2007) Upregulation of the GLN transporter through transactivation mediated by cAMP/protein kinase A signals toward exacerbation of vulnerability to oxidative stress in rat neocortical astrocytes. J Cell Physiol 212:375–385
Ogura M, Takarada T, Nakamichi N, Kawagoe H, Sako A, Nakazato R, Yoneda Y (2011) Exacerbated vulnerability to oxidative stress in astrocytic C6 glioma cells with stable overexpression of the GLN transporter slc38a1. Neurochem Int 58:504–511
Gage FH, Coates PW, Palmer TD, Kuhn HG, Fisher LJ, Suhonen JO, Peterson DA, Suhr ST, Ray J (1995) Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci USA 92:11879–11883
Suhonen JO, Peterson DA, Ray J, Gage FH (1996) Differentiation of adult hippocampus-derived progenitors into olfactory neurons in vivo. Nature 383:624–627
Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A (1999) Subventricular zone astrocytes are neural stem cell in the adult mammalian brain. Cell 97:703–716
Johansson CB, Momma S, Clarke DL, Risling M, Lendahl U, Frisen J (1999) Identification of a neural stem cell in the adult mammalian central nervous system. Cell 96:25–34
Temple S, Alvarez-Buylla A (1999) Stem cells in the adult mammalian central nervous system. Curr Opin Neurobiol 9:135–141
McBurney MW, Rogers BJ (1982) Isolation of male embryonal carcinoma cells and their chromosome replication patterns. Dev Biol 89:503–508
Jones-Villeneuve EM, McBurney MW, Rogers KA, Kalnins VI (1982) Retinoic acid induces embryonal carcinoma cells to differentiate into neurons and glial cells. J Cell Biol 94:253–262
Ogura M, Kakuda T, Takarada T, Nakamichi N, Fukumori R, Kim YH, Hinoi E, Yoneda Y (2012) Promotion of both proliferation and differentiation in pluripotent P19 cells with stable overexpression of the GLN transporter Slc38a1. PLoS ONE 7:e48270
Bertrand N, Castro DS, Guillemot F (2002) Proneural genes and the specification of neural cell types. Nat Rev Neurosci 3:517–530
Kuwabara T, Hsieh J, Muotri A, Yeo G, Warashina M, Lie DC, Moore L, Nakashima K, Asashima M, Gage FH (2009) Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis. Nat Neurosci 12:1097–1105
Gao Z, Ure K, Ables JL, Lagace DC, Nave KA, Goebbels S, Eisch AJ, Hsieh J (2009) Neurod1 is essential for the survival and maturation of adult-born neurons. Nat Neurosci 12:1090–1092
Boutin C, Hardt O, de Chevigny A, Core N, Goebbels S, Seidenfaden R, Bosio A, Cremer H (2010) NeuroD1 induces terminal neuronal differentiation in olfactory neurogenesis. Proc Natl Acad Sci USA 107:1201–1206
Casarosa S, Fode C, Guillemot F (1999) Mash1 regulates neurogenesis in the ventral telencephalon. Development 126:525–534
Kageyama R, Ohtsuka T (1999) The Notch-Hes pathway in mammalian neural development. Cell Res 9:179–188
Ohtsuka T, Ishibashi M, Gradwohl G, Nakanishi S, Guillemot F, Kageyama R (1999) Hes1 and Hes5 as notch effectors in mammalian neuronal differentiation. EMBO J 18:2196–2207
Nakajo T, Yamatsuji T, Ban H, Shigemitsu K, Haisa M, Motoki T, Noma K, Nobuhisa T, Matsuoka J, Gunduz M, Yonezawa K, Tanaka N, Naomoto Y (2005) GLN is a key regulator for amino acid-controlled cell growth through the mTOR signaling pathway in rat intestinal epithelial cells. Biochem Biophys Res Commun 326:174–180
Westergaard N, Beart PM, Schousboe A (1993) Transport of L-[3H]arginine in cultured neurons: characteristics and inhibition by nitric oxide synthase inhibitors. J Neurochem 61:364–367
Zielinska M, Ruszkiewicz J, Hilger W, Fresko I, Albrecht J (2011) Hyperammonemia increases the expression and activity of the glutamine/arginine transporter y + LAT2 in rat cerebral cortex: implications for the nitric oxide/cGMP pathway. Neurochem Int 58:190–195
Fumarola C, La Monica S, Guidotti GG (2005) Amino acid signaling through the mammalian target of rapamycin (mTOR) pathway: role of GLN and of cell shrinkage. J Cell Physiol 204:155–165
Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, Murphy LO (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136:521–534
Endo M, Antonyak MA, Cerione RA (2009) Cdc42-mTOR signaling pathway controls Nes5 and Pax6 expression in retinoic acid-dependent neural differentiation. J Biol Chem 284:5107–5118
Takarada T, Ogura M, Nakamichi N, Kakuda T, Nakazato R, Kokubo H, Ikeno S, Nakamura S, Kutsukake T, Hinoi E, Yoneda Y (2016) Upregulation of Slc38a1 gene along with promotion of neurosphere growth and subsequent neuronal specification in undifferentiated neural progenitor cells exposed to L-theanine. Neurochem Res 41:5–15
Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107:881–891
Shen X, Ellis RE, Lee K, Liu CY, Ynag K, Solomon A, Yoshida H, Morimoto R, Kumit DM, Mori K, Kaufman RJ (2001) Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development. Cell 107:893–903
Crespo I, San-Miguel B, Prause C, Marroni N, Cuevas MJ, Gonzalez-Gallego H, Tunon MJ (2012) GLN treatment attenuates endoplasmic reticulum stress and apoptosis in TNBS-induced colitis. PLoS ONE 7:e50407
Curi R, Lagranha CJ, Doi SQ, Sellitti DF, Procopio J, Pithon-Curi TC, Corless M, Newsholme P (2005) Molecular mechanisms of GLN action. J Cell Physiol 204:392–401
Yamauchi K, Komatsu T, Kulkarni AD, Ohmori Y, Minami H, Ushiyama Y, Nakayama M, Yamamoto S (2002) GLN and arginine affect Caco-2 cell proliferation by promotion of nucleotide synthesis. Nutrition 18:329–333
Yoneyama M, Fukui M, Nakamichi N, Kitayama T, Taniura H, Yoneda Y (2007) Activation of GABAA receptors facilitates astroglial differentiation induced by ciliary neurotrophic factor in neural progenitors isolated from fetal rat brain. J Neurochem 100:1667–1679
Fukui M, Nakamichi N, Yoneyama M, Ozawa S, Fujimori S, Takahata Y, Nakamura N, Taniura H, Yoneda Y (2008) Modulation of cellular proliferation and differentiation through GABAB receptors expressed by undifferentiated neural progenitor cells isolated from fetal mouse brain. J Cell Physiol 216:507–519
Kitayama T, Yoneyama M, Yoneda Y (2003) Possible regulation by N-methyl-D-aspartate receptors of proliferative progenitor cells expressed in adult mouse hippocampal dentate gyrus. J Neurochem 84:767–780
Kitayama T, Yoneyama M, Tamaki K, Yoneda Y (2004) Regulation of neuronal differentiation by N-methyl-D-aspartate receptors expressed in neural progenitor cells isolated from adult mouse hippocampus. J Neurosci Res 76:599–612
Takarada T, Nakamichi N, Nakazato R, Kakuda T, Kokubo H, Ikeno S, Nakamura S, Kuramoto N, Hinoi E, Yoneda Y (2016) Possible activation by the green tea amino acid L-theanine of mammalian target of rapamycin signaling in undifferentiated neural progenitor cells in vitro. Biochem Biophys Rep 5:89–95
Takeda A, Sakamoto K, Tamano H, Fukura K, Inui N, Suh SW, Won SJ, Yokogishi H (2011) Facilitated neurogenesis in the developing hippocampus after intake of L-theanine, an amino acid in tea leaves, and object recognition memory. Cell Mol Neurobiol 31:1079–1088
Mignone JL, Kukekov V, Chiang AS, Steindler D, Enikolopov G (2004) Neural stem and progenitor cells in nestin-GFP transgenic mice. J Comp Neurol 469:311–324
Yoneda Y, Kanmori K, Ida S, Kuriyama K (1983) Stress-induced alterations in metabolism of gamma-aminobutyric acid in rat brain. J Neurochem 40:350–356
Tamaki K, Yamada K, Nakamichi N, Taniura H, Yoneda Y (2008) Transient suppression of progenitor cell proliferation through NMDA receptors in hippocampal dentate gyrus of mice with traumatic stress experience. J Neurochem 105:1642–1655
Sairanen M, Lucas G, Ernfors P, Castren M, Castren E (2005) Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci 25:1089–1094
Li Y, Luikart BW, Bimbaum S, Chen J, Kwon CH, Kemie SG, Bassel-Duby R, Parada LF (2009) TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressant treatment. Neuron 59:399–412
Li Y, Li Y, McKay RM, Riethmacher D, Parada LF (2012) Neurofibromin modulates adult neurogenesis and behavioral effects of antidepressants. J Neurosci 32:3529–3539
Takarada T, Nakamichi N, Kakuda T, Nakazato R, Kokubo H, Ikeno S, Nakamura S, Hinoi S, Yoneda Y (2015) Daily oral intake of L-theanine prevents the decline of 5-bromo-2′-deoxyuridine incorporation in hippocampal dentate gyrus with concomitant alleviation of behavioral abnormalities in adult mice with severe traumatic stress. J Pharmacol Sci 127:292–297
Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293
Duran RV, Oppliger W, Robitaille AM, Heiserich L, Skendaj R, Gottlieb E, Hall MN (2012) Glutaminolysis activates Rag-mTORC1 signaling. Mol Cell 47:349–358
Kataoka Y, Ustunomiya K, Kimbara N, Fukushima K, Mori T, Shiba J, Utsunomiya S, Hasebe Y, Nishida K, Hamamoto K, Furukawa S, Okuda H, Mizuno K, Baba Y, Nozawa A, Kataoka K, Kakuda T (2009) Preventive effect of green tea containing L-theanine at a high concentration on dementia in aged volunteers. J Mibyou Sys Ass 15:17–23 (in Japanese)
Noguchi-Shinohara M, Yuki S, Dohmoto C, Ikeda Y, Samuraki M, Iwasa K, Yokogawa M, Asai K, Komai K, Nakamura H, Yamada M (2014) Consumption of green tea, but not black tea or coffee, is associated with reduced risk of cognitive decline. PLoS ONE 9:e96013
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The author has no conflicts of interest to declare.
Rights and permissions
About this article
Cite this article
Yoneda, Y. An l-Glutamine Transporter Isoform for Neurogenesis Facilitated by l-Theanine. Neurochem Res 42, 2686–2697 (2017). https://doi.org/10.1007/s11064-017-2317-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-017-2317-6