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Transport of Amino Acid Neurotransmitters into Synaptic Vesicles

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Presynaptic Terminals

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Abstract

Fast chemical neurotransmission at the synapse is mediated by the release of neurotransmitters from synaptic vesicles (SVs) by exocytosis. In the mammalian central nervous system, the majority of neurons utilize amino acids such as glutamate, γ-aminobutyric acid (GABA), and glycine. Glutamate is the major excitatory neurotransmitter, whereas GABA and glycine are inhibitory. These amino acids are present at relatively high levels in the cytoplasm of presynaptic terminals and are accumulated into SVs for their exocytotic release. Over the past several decades, this essential process has been biochemically characterized and proteins responsible for neurotransmitter loading have been molecularly identified. Analysis of knockout animals has elucidated physiological significance of this process and moreover has deepened our understanding of glutamatergic and GABAergic neural circuits. However, the precise mechanism of the transport system remains largely unknown. In this chapter, I overview advances in the vesicular loading process and discuss some controversial concepts that may have important consequences for synaptic transmission.

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References

  • Ahdut-Hacohen R, Duridanova D, Meiri H, Rahamimoff R (2004) Hydrogen ions control synaptic vesicle ion channel activity in Torpedo electromotor neurones. J Physiol 556:347–352

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Akil O, Seal RP, Burke K, Wang C, Alemi A, During M, Edwards RH, Lustig LR (2012) Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy. Neuron 75:283–293

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bedet C, Isambert MF, Henry JP, Gasnier B (2000) Constitutive phosphorylation of the vesicular inhibitory amino acid transporter in rat central nervous system. J Neurochem 75:1654–1663

    Article  CAS  PubMed  Google Scholar 

  • Bellocchio EE, Hu H, Pohorille A, Chan J, Pickel VM, Edwards RH (1998) The localization of the brain-specific inorganic phosphate transporter suggests a specific presynaptic role in glutamatergic transmission. J Neurosci 18:8648–8659

    CAS  PubMed  Google Scholar 

  • Bellocchio EE, Reimer RJ, Fremeau RT Jr, Edwards RH (2000) Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter. Science 289:957–960

    Article  CAS  PubMed  Google Scholar 

  • Burger PM, Hell J, Mehl E, Krasel C, Lottspeich F, Jahn R (1991) GABA and glycine in synaptic vesicles: storage and transport characteristics. Neuron 7:287–293

    Article  CAS  PubMed  Google Scholar 

  • Carlson MD, Kish PE, Ueda T (1989) Characterization of the solubilized and reconstituted ATP-dependent vesicular glutamate uptake system. J Biol Chem 264:7369–7376

    CAS  PubMed  Google Scholar 

  • Chaudhry FA, Reimer RJ, Bellocchio EE, Danbolt NC, Osen KK, Edwards RH, Storm-Mathisen J (1998) The vesicular GABA transporter, VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABAergic neurons. J Neurosci 18:9733–9750

    CAS  PubMed  Google Scholar 

  • Daniels RW, Collins CA, Gelfand MV, Dant J, Brooks ES, Krantz DE, DiAntonio A (2004) Increased expression of the Drosophila vesicular glutamate transporter leads to excess glutamate release and a compensatory decrease in quantal content. J Neurosci 24:10466–10474

    Article  CAS  PubMed  Google Scholar 

  • Daniels RW, Collins CA, Chen K, Gelfand MV, Featherstone DE, DiAntonio A (2006) A single vesicular glutamate transporter is sufficient to fill a synaptic vesicle. Neuron 49:11–16

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Edwards RH (2007) The neurotransmitter cycle and quantal size. Neuron 55:835–858

    Article  CAS  PubMed  Google Scholar 

  • Foss SM, Li H, Santos MS, Edwards RH, Voglmaier SM (2013) Multiple dileucine-like motifs direct VGLUT1 trafficking. J Neurosci 33:10647–10660

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fremeau RT Jr, Troyer MD, Pahner I, Nygaard GO, Tran CH, Reimer RJ, Bellocchio EE, Fortin D, Storm-Mathisen J, Edwards RH (2001) The expression of vesicular glutamate transporters defines two classes of excitatory synapse. Neuron 31:247–260

    Article  CAS  PubMed  Google Scholar 

  • Fremeau RT Jr, Burman J, Qureshi T, Tran CH, Proctor J, Johnson J, Zhang H, Sulzer D, Copenhagen DR, Storm-Mathisen J et al (2002) The identification of vesicular glutamate transporter 3 suggests novel modes of signaling by glutamate. Proc Natl Acad Sci U S A 99:14488–14493

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fremeau RT Jr, Kam K, Qureshi T, Johnson J, Copenhagen DR, Storm-Mathisen J, Chaudhry FA, Nicoll RA, Edwards RH (2004) Vesicular glutamate transporters 1 and 2 target to functionally distinct synaptic release sites. Science 304:1815–1819

    Article  CAS  PubMed  Google Scholar 

  • Fujiyama F, Furuta T, Kaneko T (2001) Immunocytochemical localization of candidates for vesicular glutamate transporters in the rat cerebral cortex. J Comp Neurol 435:379–387

    Article  CAS  PubMed  Google Scholar 

  • Fykse EM, Christensen H, Fonnum F (1989) Comparison of the properties of gamma-aminobutyric acid and L-glutamate uptake into synaptic vesicles isolated from rat brain. J Neurochem 52:946–951

    Article  CAS  PubMed  Google Scholar 

  • Goh GY, Huang H, Ullman J, Borre L, Hnasko TS, Trussell LO, Edwards RH (2011) Presynaptic regulation of quantal size: K+/H + exchange stimulates vesicular glutamate transport. Nat Neurosci 14:1285–1292

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Goncalves PP, Meireles SM, Neves P, Vale MG (1999a) Ionic selectivity of the Ca2+/H+ antiport in synaptic vesicles of sheep brain cortex. Brain Res Mol Brain Res 67:283–291

    Article  CAS  PubMed  Google Scholar 

  • Goncalves PP, Meireles SM, Neves P, Vale MG (1999b) Synaptic vesicle Ca2+/H+ antiport: dependence on the proton electrochemical gradient. Brain Res Mol Brain Res 71:178–184

    Article  CAS  PubMed  Google Scholar 

  • Grabe M, Oster G (2001) Regulation of organelle acidity. J Gen Physiol 117:329–344

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gras C, Amilhon B, Lepicard EM, Poirel O, Vinatier J, Herbin M, Dumas S, Tzavara ET, Wade MR, Nomikos GG et al (2008) The vesicular glutamate transporter VGLUT3 synergizes striatal acetylcholine tone. Nat Neurosci 11:292–300

    Article  CAS  PubMed  Google Scholar 

  • Gronborg M, Pavlos NJ, Brunk I, Chua JJ, Munster-Wandowski A, Riedel D, Ahnert-Hilger G, Urlaub H, Jahn R (2010) Quantitative comparison of glutamatergic and GABAergic synaptic vesicles unveils selectivity for few proteins including MAL2, a novel synaptic vesicle protein. J Neurosci 30:2–12

    Article  CAS  PubMed  Google Scholar 

  • Hartinger J, Jahn R (1993) An anion binding site that regulates the glutamate transporter of synaptic vesicles. J Biol Chem 268:23122–23127

    CAS  PubMed  Google Scholar 

  • Hell JW, Maycox PR, Stadler H, Jahn R (1988) Uptake of GABA by rat brain synaptic vesicles isolated by a new procedure. EMBO J 7:3023–3029

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hell JW, Maycox PR, Jahn R (1990) Energy dependence and functional reconstitution of the gamma-aminobutyric acid carrier from synaptic vesicles. J Biol Chem 265:2111–2117

    CAS  PubMed  Google Scholar 

  • Hell JW, Edelmann L, Hartinger J, Jahn R (1991) Functional reconstitution of the gamma-aminobutyric acid transporter from synaptic vesicles using artificial ion gradients. Biochemistry 30:11795–11800

    Article  CAS  PubMed  Google Scholar 

  • Hnasko TS, Chuhma N, Zhang H, Goh GY, Sulzer D, Palmiter RD, Rayport S, Edwards RH (2010) Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo. Neuron 65:643–656

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hori T, Takahashi T (2012) Kinetics of synaptic vesicle refilling with neurotransmitter glutamate. Neuron 76:511–517

    Article  CAS  PubMed  Google Scholar 

  • Ikeda K, Bekkers JM (2009) Counting the number of releasable synaptic vesicles in a presynaptic terminal. Proc Natl Acad Sci U S A 106:2945–2950

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ishikawa T, Sahara Y, Takahashi T (2002) A single packet of transmitter does not saturate postsynaptic glutamate receptors. Neuron 34:613–621

    Article  CAS  PubMed  Google Scholar 

  • Juge N, Muroyama A, Hiasa M, Omote H, Moriyama Y (2009) Vesicular inhibitory amino acid transporter is a Cl-/gamma-aminobutyrate Co-transporter. J Biol Chem 284:35073–35078

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Juge N, Gray JA, Omote H, Miyaji T, Inoue T, Hara C, Uneyama H, Edwards RH, Nicoll RA, Moriyama Y (2010) Metabolic control of vesicular glutamate transport and release. Neuron 68:99–112

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kish PE, Fischer-Bovenkerk C, Ueda T (1989) Active transport of gamma-aminobutyric acid and glycine into synaptic vesicles. Proc Natl Acad Sci U S A 86:3877–3881

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Leo S, Moechars D, Callaerts-Vegh Z, D’Hooge R, Meert T (2009) Impairment of VGLUT2 but not VGLUT1 signaling reduces neuropathy-induced hypersensitivity. Eur J Pain 13:1008–1017

    Article  CAS  PubMed  Google Scholar 

  • Maycox PR, Deckwerth T, Hell JW, Jahn R (1988) Glutamate uptake by brain synaptic vesicles. Energy dependence of transport and functional reconstitution in proteoliposomes. J Biol Chem 263:15423–15428

    CAS  PubMed  Google Scholar 

  • McIntire SL, Reimer RJ, Schuske K, Edwards RH, Jorgensen EM (1997) Identification and characterization of the vesicular GABA transporter. Nature 389:870–876

    Article  CAS  PubMed  Google Scholar 

  • Miesenbock G, De Angelis DA, Rothman JE (1998) Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins. Nature 394:192–195

    Article  CAS  PubMed  Google Scholar 

  • Miyazaki T, Fukaya M, Shimizu H, Watanabe M (2003) Subtype switching of vesicular glutamate transporters at parallel fibre-Purkinje cell synapses in developing mouse cerebellum. Eur J Neurosci 17:2563–2572

    Article  PubMed  Google Scholar 

  • Moechars D, Weston MC, Leo S, Callaerts-Vegh Z, Goris I, Daneels G, Buist A, Cik M, van der Spek P, Kass S et al (2006) Vesicular glutamate transporter VGLUT2 expression levels control quantal size and neuropathic pain. J Neurosci 26:12055–12066

    Article  CAS  PubMed  Google Scholar 

  • Moriyama Y, Nelson N (1987) The purified ATPase from chromaffin granule membranes is an anion-dependent proton pump. J Biol Chem 262:9175–9180

    CAS  PubMed  Google Scholar 

  • Moriyama Y, Maeda M, Futai M (1990) Energy coupling of L-glutamate transport and vacuolar H(+)-ATPase in brain synaptic vesicles. J Biochem 108:689–693

    CAS  PubMed  Google Scholar 

  • Moriyama Y, Maeda M, Futai M (1992) The role of V-ATPase in neuronal and endocrine systems. J Exp Biol 172:171–178

    CAS  PubMed  Google Scholar 

  • Naito S, Ueda T (1983) Adenosine triphosphate-dependent uptake of glutamate into protein I-associated synaptic vesicles. J Biol Chem 258:696–699

    CAS  PubMed  Google Scholar 

  • Naito S, Ueda T (1985) Characterization of glutamate uptake into synaptic vesicles. J Neurochem 44:99–109

    Article  CAS  PubMed  Google Scholar 

  • Nakamura K, Hioki H, Fujiyama F, Kaneko T (2005) Postnatal changes of vesicular glutamate transporter (VGluT)1 and VGluT2 immunoreactivities and their colocalization in the mouse forebrain. J Comp Neurol 492:263–288

    Article  CAS  PubMed  Google Scholar 

  • Nelson N, Sacher A, Nelson H (2002) The significance of molecular slips in transport systems. Nat Rev Mol Cell Biol 3:876–881

    Article  CAS  PubMed  Google Scholar 

  • Riazanski V, Deriy LV, Shevchenko PD, Le B, Gomez EA, Nelson DJ (2011) Presynaptic CLC-3 determines quantal size of inhibitory transmission in the hippocampus. Nat Neurosci 14:487–494

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rousseau F, Aubrey KR, Supplisson S (2008) The glycine transporter GlyT2 controls the dynamics of synaptic vesicle refilling in inhibitory spinal cord neurons. J Neurosci 28:9755–9768

    Article  CAS  PubMed  Google Scholar 

  • Ruel J, Emery S, Nouvian R, Bersot T, Amilhon B, Van Rybroek JM, Rebillard G, Lenoir M, Eybalin M, Delprat B et al (2008) Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice. Am J Hum Genet 83:278–292

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sagne C, El Mestikawy S, Isambert MF, Hamon M, Henry JP, Giros B, Gasnier B (1997) Cloning of a functional vesicular GABA and glycine transporter by screening of genome databases. FEBS Lett 417:177–183

    Article  CAS  PubMed  Google Scholar 

  • Saito K, Kakizaki T, Hayashi R, Nishimaru H, Furukawa T, Nakazato Y, Takamori S, Ebihara S, Uematsu M, Mishina M et al (2010) The physiological roles of vesicular GABA transporter during embryonic development: a study using knockout mice. Mol Brain 3:40

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sankaranarayanan S, Ryan TA (2001) Calcium accelerates endocytosis of vSNAREs at hippocampal synapses. Nat Neurosci 4:129–136

    Article  CAS  PubMed  Google Scholar 

  • Santos MS, Park CK, Foss SM, Li H, Voglmaier SM (2013) Sorting of the vesicular GABA transporter to functional vesicle pools by an atypical dileucine-like motif. J Neurosci 33:10634–10646

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sato M, Inoue K, Kasai M (1992) Ion channels on synaptic vesicle membranes studied by planar lipid bilayer method. Biophys J 63:1500–1505

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Schallier A, Massie A, Loyens E, Moechars D, Drinkenburg W, Michotte Y, Smolders I (2009) vGLUT2 heterozygous mice show more susceptibility to clonic seizures induced by pentylenetetrazol. Neurochem Int 55:41–44

    Article  CAS  PubMed  Google Scholar 

  • Schenck S, Wojcik SM, Brose N, Takamori S (2009) A chloride conductance in VGLUT1 underlies maximal glutamate loading into synaptic vesicles. Nat Neurosci 12:156–162

    Article  CAS  PubMed  Google Scholar 

  • Seal RP, Akil O, Yi E, Weber CM, Grant L, Yoo J, Clause A, Kandler K, Noebels JL, Glowatzki E et al (2008) Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3. Neuron 57:263–275

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shioi J, Ueda T (1990) Artificially imposed electrical potentials drive L-glutamate uptake into synaptic vesicles of bovine cerebral cortex. Biochem J 267:63–68

    CAS  PubMed Central  PubMed  Google Scholar 

  • Stauber T, Jentsch TJ (2013) Chloride in vesicular trafficking and function. Annu Rev Physiol 75:453–477

    Article  CAS  PubMed  Google Scholar 

  • Stobrawa SM, Breiderhoff T, Takamori S, Engel D, Schweizer M, Zdebik AA, Bosl MR, Ruether K, Jahn H, Draguhn A et al (2001) Disruption of ClC-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus. Neuron 29:185–196

    Article  CAS  PubMed  Google Scholar 

  • Tabb JS, Kish PE, Van Dyke R, Ueda T (1992) Glutamate transport into synaptic vesicles. Roles of membrane potential, pH gradient, and intravesicular pH. J Biol Chem 267:15412–15418

    CAS  PubMed  Google Scholar 

  • Takamori S (2006) VGLUTs: ‘exciting’ times for glutamatergic research? Neurosci Res 55:343–351

    Article  CAS  PubMed  Google Scholar 

  • Takamori S, Rhee JS, Rosenmund C, Jahn R (2000a) Identification of a vesicular glutamate transporter that defines a glutamatergic phenotype in neurons. Nature 407:189–194

    Article  CAS  PubMed  Google Scholar 

  • Takamori S, Riedel D, Jahn R (2000b) Immunoisolation of GABA-specific synaptic vesicles defines a functionally distinct subset of synaptic vesicles. J Neurosci 20:4904–4911

    CAS  PubMed  Google Scholar 

  • Takamori S, Holt M, Stenius K, Lemke EA, Gronborg M, Riedel D, Urlaub H, Schenck S, Brugger B, Ringler P et al (2006) Molecular anatomy of a trafficking organelle. Cell 127:831–846

    Article  CAS  PubMed  Google Scholar 

  • Tordera RM, Totterdell S, Wojcik SM, Brose N, Elizalde N, Lasheras B, Del Rio J (2007) Enhanced anxiety, depressive-like behaviour and impaired recognition memory in mice with reduced expression of the vesicular glutamate transporter 1 (VGLUT1). Eur J Neurosci 25:281–290

    Article  CAS  PubMed  Google Scholar 

  • Voglmaier SM, Kam K, Yang H, Fortin DL, Hua Z, Nicoll RA, Edwards RH (2006) Distinct endocytic pathways control the rate and extent of synaptic vesicle protein recycling. Neuron 51:71–84

    Article  CAS  PubMed  Google Scholar 

  • Wallen-Mackenzie A, Gezelius H, Thoby-Brisson M, Nygard A, Enjin A, Fujiyama F, Fortin G, Kullander K (2006) Vesicular glutamate transporter 2 is required for central respiratory rhythm generation but not for locomotor central pattern generation. J Neurosci 26:12294–12307

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Kakizaki T, Sakagami H, Saito K, Ebihara S, Kato M, Hirabayashi M, Saito Y, Furuya N, Yanagawa Y (2009) Fluorescent labeling of both GABAergic and glycinergic neurons in vesicular GABA transporter (VGAT)-venus transgenic mouse. Neuroscience 164:1031–1043

    Article  CAS  PubMed  Google Scholar 

  • Weston MC, Nehring RB, Wojcik SM, Rosenmund C (2011) Interplay between VGLUT isoforms and endophilin A1 regulates neurotransmitter release and short-term plasticity. Neuron 69:1147–1159

    Article  CAS  PubMed  Google Scholar 

  • Wilson NR, Kang J, Hueske EV, Leung T, Varoqui H, Murnick JG, Erickson JD, Liu G (2005) Presynaptic regulation of quantal size by the vesicular glutamate transporter VGLUT1. J Neurosci 25:6221–6234

    Article  CAS  PubMed  Google Scholar 

  • Wojcik SM, Rhee JS, Herzog E, Sigler A, Jahn R, Takamori S, Brose N, Rosenmund C (2004) An essential role for vesicular glutamate transporter 1 (VGLUT1) in postnatal development and control of quantal size. Proc Natl Acad Sci U S A 101:7158–7163

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wojcik SM, Katsurabayashi S, Guillemin I, Friauf E, Rosenmund C, Brose N, Rhee JS (2006) A shared vesicular carrier allows synaptic corelease of GABA and glycine. Neuron 50:575–587

    Article  CAS  PubMed  Google Scholar 

  • Wolosker H, de Souza DO, de Meis L (1996) Regulation of glutamate transport into synaptic vesicles by chloride and proton gradient. J Biol Chem 271:11726–11731

    Article  CAS  PubMed  Google Scholar 

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  1. Laboratory of Neural Membrane Biology, Graduate School of Brain Science, Doshisha University, Kyoto, Japan

    Shigeo Takamori

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Correspondence to Shigeo Takamori .

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  1. Department of Physiology, Tokyo Medical University, Tokyo, Japan

    Sumiko Mochida

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Takamori, S. (2015). Transport of Amino Acid Neurotransmitters into Synaptic Vesicles. In: Mochida, S. (eds) Presynaptic Terminals. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55166-9_12

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