Skip to main content
Log in

Glutamate Release

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Our aim was to review the processes of glutamate release from both biochemical and neurophysiological points of view. A large body of evidence now indicates that glutamate is specifically accumulated into synaptic vesicles, which provides strong support for the concept that glutamate is released from synaptic vesicles and is the major excitatory neurotransmitter. Evidence suggests the notion that synaptic vesicles, in order to sustain the neurotransmitter pool of glutamate, are endowed with an efficient mechanism for vesicular filling of glutamate. Glutamate-loaded vesicles undergo removal of Synapsin I by CaM kinase II-mediated phosphorylation, transforming to the release-ready pool. Vesicle docking to and fusion with the presynaptic plasma membrane are thought to be mediated by the SNARE complex. The Ca2+-dependent step in exocytosis is proposed to be mediated by synaptotagmin.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

AAT:

Aspartate aminotransferase

CNS:

Central nervous system

CaM-PK:

Calmodulin-dependent protein kinase

GABA:

γ-Aminobutyric acid

mepp:

Miniature end-plate potential

RIM:

Rab3 interacting molecule

RIM-BP:

RIM-binding protein

SNARE:

Soluble N-ethylmaleimide-sensitive factor attachment protein receptor

TCA:

Tricarboxylic acid

VGLUT:

Vesicular glutamate transporter

References

  1. Ramon y Cajal S (1995) Histology of the nervous system, vol 2. Oxford University Press, p 121

  2. Sherrington CS (1897) The central nervous system. In: Foster M (ed) A textbook of physiology, vol 3. MacMillan, London

    Google Scholar 

  3. Loewi O (1921) Uber humorale ubertragbarkeit der Herznervenwirkung. Pflugers Arch Physiolog 189:239–242

    Article  Google Scholar 

  4. Eccles JC (1964) The physiology of synapses. Springer, Berlin-Gottingen-Heidelberg

    Book  Google Scholar 

  5. Fatt P, Katz B (1950) Some observations on biological noise. Nature 166:597–598

    Article  CAS  PubMed  Google Scholar 

  6. Del Castillo J, Katz B (1954) Quantal components of the endplate potential. J Physiol 124:560–573

    Article  PubMed Central  Google Scholar 

  7. Ling G, Gerard RW (1949) The normal membrane potential of frog sartorius fibers. J. Cell Comp Physiol 34:383–396

    Article  CAS  Google Scholar 

  8. Elmqvist D, Quastel DMJ (1965) Presynaptic action of hemicholinium at the neuromuscular junction. J Physiol 177:463–482

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Fernandez JM, Neher E, Gomperts BD (1984) Capacitance measurements reveal stepwise fusion events in degranulating mast cells. Nature 312:453–455

    Article  CAS  PubMed  Google Scholar 

  10. Wightman RM, Jankowski JA, Kennedy RT, Kawagoe KT, Schroeder TJ, Leszczyszyn DJ, Near JA, Diliberto EJ Jr, Viveros OH (1991) Temporally resolved catecholamine spikes correspond to single vesicle release from individual chromaffin cells. Proc Natl Acad Sci USA 88:10754–10758

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Alabi AA, Tsien RW (2013) Perspectives on kiss-and-run: role in exocytosis, endocytosis, and neurotransmission. Annu Rev Physiol 75:393–422

    Article  CAS  PubMed  Google Scholar 

  12. De Robertis E (1956) Submicroscopic changes of the synapse after nerve section in the acoustic ganglion of the guinea pig. J Biophys Biochem Cytol 2:503–512

    Article  PubMed Central  Google Scholar 

  13. Gray EG (1959) Axo-somatic and axo-dendritic synapses of the cerebral cortex: and electron microscope study. J Anat 93:420–433

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Whittaker VP, Gray EG (1962) The synapse: biology and morphology. Brit Med Bull 18:223–228

    CAS  PubMed  Google Scholar 

  15. Whittaker VP, Michaelson IA, Kirkland RJ (1964) The separation of synaptic vesicles from nerve-ending particles (‘synaptosomes’). Biochem J 90:293

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. 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 

  17. Fatt P, Katz B (1953) The effect of inhibitory nerve impulses on a crustacean muscle fibre. J Physiol 121:374–389

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Dudel J, Orkand RK (1960) Spontaneous potential changes at crayfish neuromuscular junctions. Nature 186:476–477

    Article  CAS  PubMed  Google Scholar 

  19. Katz B, Miledi R (1963) A study of spontaneous miniature potentials in spinal motoneurones. J Physiol 168:389–422

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Miledi R (1967) Spontaneous synaptic potentials and quantal release of transmitter in the stellate ganglion of the squid. J Physiol 192:379–406

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Curtis DR, Phillis JW, Watkins JC (1960) The chemical excitation of spinal neurones by certain acidic amino acids. J Physiol 150:656–682

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Curtis DR, Phillis JW, Watkins JC (1961) Actions of aminoacids on the isolated hemisected spinal cord of the toad. Brit J Pharmacol Chemotherapy 16:262–283

    Article  CAS  Google Scholar 

  23. Krenjevic K, Phillis JW (1963) Actions of certain amines on cerebral cortical neurones. Brit J Pharmacol Chemotherapy 20:471–479

    Article  Google Scholar 

  24. Curtis DR, Davis R (1963) The excitation of lateral geniculate neurones by quaternary ammonium derivatives. J Physiol 165:62–82

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Hackett JT, Hou SM, Cochran SL (1979) Glutamate and synaptic depolarization of Purkinje cells evoked by parallel fibers and by climbing fibers. Brain Res 170:377–380

    Article  CAS  PubMed  Google Scholar 

  26. Mangan JL, Whittaker VP (1966) The distribution of free amino acids in subcellular fractions of guinea-pig brain. Biochem J 98:128–137

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Rassin DK (1972) Amino acids as putative transmitters: failure to bind to synaptic vesicles of guinea pig cerebral cortex. J Neurochem 19:139–148

    Article  CAS  PubMed  Google Scholar 

  28. Kontro P, Marnela KM, Oja SS (1980) Free amino acids in the synaptosome and synaptic vesicle fractions of different bovine brain areas. Brain Res 184:129–141

    Article  CAS  PubMed  Google Scholar 

  29. De Belleroche JS, Bradford HF (1973) Amino acids in synaptic vesicles from mammalian cerebral cortex: a reappraisal. J Neurochem 21:441–451

    Article  PubMed  Google Scholar 

  30. De Belleroche JS, Bradford HF (1977) On the site of origin of transmitter amino acids released by depolarization of nerve terminals in vitro. J Neurochem 29:335–343

    Article  PubMed  Google Scholar 

  31. De Belleroche JS, Bradford HF (1972) Metabolism of beds of mammalian cortical synaptosomes: response to depolarizing influences. J Neurochem 19:585–602

    Article  PubMed  Google Scholar 

  32. Sandoval ME, Horch P, Cotman CW (1978) Evaluation of glutamate as a hippocampal neurotransmitter: glutamate uptake and release from synaptosomes. Brain Res 142:285–299

    Article  CAS  PubMed  Google Scholar 

  33. Hamberger AC, Chiang GH, Nylén ES, Scheff SW, Cotman CW (1979) Glutamate as a CNS transmitter. I. Evaluation of glucose and glutamine as precursors for the synthesis of preferentially released glutamate. Brain Res 168:513–530

    Article  CAS  PubMed  Google Scholar 

  34. Nicholls DG, Sihra TS (1986) Synaptosomes possess an exocytotic pool of glutamate. Nature 321:772–773

    Article  CAS  PubMed  Google Scholar 

  35. Tibbs GR, Barrie AI, Van-Mieghem F, McMahon HT, Nicholls DG (1989) Repetitive action potentials in isolated nerve terminals in the presence of 4-aminopyridine: effects on cytosolic free Ca2+ and glutamate release. J Neurochem 53:1693–1699

    Article  CAS  PubMed  Google Scholar 

  36. Nicholls DG, Attwell D (1990) The release and uptake of excitatory amino acids. Trends Pharmacol Sci 11:462–468

    Article  PubMed  Google Scholar 

  37. Naito S, Ueda T (1981) Affinity-purified anti-protein I antibody. Specific inhibitor of phosphorylation of protein I, a synaptic protein. J Biol Chem 256:10657–10663

    CAS  PubMed  Google Scholar 

  38. Ueda T, Greengard P (1977) Adenosine 3′:5′-monophosphate-regulated phosphoprotein system of neuronal membranes. I. Solubilization, purification, and some properties of an endogenous phosphoprotein. J Biol Chem 252:5155–5163

    CAS  PubMed  Google Scholar 

  39. Ueda T, Greengard P, Berzins K, Cohen RS, Blomberg F, Grab DJ, Siekevitz P (1979) Subcellular distribution in cerebral cortex of two proteins phosphorylated by a cAMP-dependent protein kinase. J Cell Biol 83:308–319

    Article  CAS  PubMed  Google Scholar 

  40. Bloom FE, Ueda T, Battenberg E, Greengard P (1979) Immunocytochemical localization, in synapses, of protein I, an endogenous substrate for protein kinases in mammalian brain. Proc Natl Acad Sci USA 76:5982–5986

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. De Camilli P, Harris SM Jr, Huttner WB, Greengard P (1983) Synapsin I (Protein I), a nerve terminal-specific phosphoprotein. II. Its specific association with synaptic vesicles demonstrated by immunocytochemistry in agarose-embedded synaptosomes. J Cell Biol 96:1355–1373

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  43. Disbrow JK, Gershten MJ, Ruth JA (1982) Uptake of l-[3H] glutamic acid by crude and purified synaptic vesicles from rat brain. Biochem Biophys Res Commun 108:1221–1227

    Article  CAS  PubMed  Google Scholar 

  44. Storm-Mathisen J, Leknes AK, Bore AT, Vaaland JL, Edminson P, Haug E-MS, Ottersen OP (1983) First visualization of glutamate and GABA in neurons by immunocytochemistry. Nature 301:517–520

    Article  CAS  PubMed  Google Scholar 

  45. 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 

  46. Burger PM, Mehl E, Cameron PL, Maycox PR, Baumert M, Lottspeich F, De Camilli P, Jahn R (1989) Synaptic vesicles immunoisolated from rat cerebral cortex contain high levels of glutamate. Neuron 3:715–720

    Article  CAS  PubMed  Google Scholar 

  47. Carlson MD, Ueda T (1990) Accumulated glutamate levels in the synaptic vesicle are not maintained in the absence of active transport. Neurosci Lett 110:325–330

    Article  CAS  PubMed  Google Scholar 

  48. 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 

  49. 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 

  50. Tabb JS, Ueda T (1991) Phylogenetic studies on the synaptic vesicle glutamate transport system. J Neurosci 11:1822–1828

    CAS  PubMed  Google Scholar 

  51. 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 

  52. Moriyama Y, Yamamoto A (1995) Vesicular l-glutamate transporter in microvesicles from bovine pineal glands. J Biol Chem 270:22314–22320

    Article  CAS  PubMed  Google Scholar 

  53. 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 

  54. Ozkan ED, Ueda T (1998) Glutamate transport and storage in synaptic vesicles. Jpn J Pharmacol 77:1–10

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. 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 

  58. Bai L, Xu H, Collins JF, Ghishan FK (2001) Molecular and functional analysis of a novel neuronal vesicular glutamate transporter. J Biol Chem 276:36764–36769

    Article  CAS  PubMed  Google Scholar 

  59. Herzog E, Bellenchi GC, Gras C, Bernard V, Ravassard P, Bedet C, Gasnier B, Giros B, El Mestikawy S (2001) The existence of a second vesicular glutamate transporter specifies subpopulations of glutamatergic neurons. J Neurosci 21:RC181

    CAS  PubMed  Google Scholar 

  60. Varoqui H, Schafer MK-H, Zhu H, Weihe E, Erickson JD (2002) Identification of the differentiation-associated Na+/Pi transporter as a novel vesicular glutamate transporter expressed in a distinct set of glutamatergic synapses. J Neurosci 22:142–155

    CAS  PubMed  Google Scholar 

  61. Takamori S, Malherbe P, Broger C, Jahn R (2002) Molecular cloning and functional characterization of human vesicular glutamate transporter 3. EMBO Rep 3:798–803

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Schafer MK-H, Varoqui H, Defamie N, Weihe E, Erickson JD (2002) Molecular cloning and functional identification of mouse vesicular glutamate transporter 3 and its expression in subsets of novel excitatory neurons. J Biol Chem 277:50734–50748

    Article  PubMed  Google Scholar 

  63. Juge N, Yoshida Y, Yatsushiro S, Omote H, Moriyama Y (2006) Vesicular glutamate transporter contains two independent transport machineries. J Biol Chem 281:39499–39506

    Article  CAS  PubMed  Google Scholar 

  64. 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 

  65. Omote H, Miyaji T, Juge N, Moriyama Y (2011) Vesicular neurotransmitter transporter: bioenergetics and regulation of glutamate transport. Biochemistry 50:5558–5565

    Article  CAS  PubMed  Google Scholar 

  66. Fischer-Bovenkerk C, Kish PE, Ueda T (1988) ATP-dependent glutamate uptake into synaptic vesicles from cerebellar mutant mice. J Neurochem 51:1054–1059

    Article  CAS  PubMed  Google Scholar 

  67. Takamori S, Rhee JS, Rosenmund C, Jahn R (2001) Identification of differentiation-associated brain-specific phosphate transporter as a second vesicular glutamate transporter (VGLUT2). J Neurosci 21:182

    Google Scholar 

  68. Hayashi M, Otsuka M, Morimoto R, Hirota S, Yatsushiro S, Takeda J, Yamamoto A, Moriyama Y (2001) Differentiation-associated Na+-dependent inorganic phosphate cotransporter (DNPI) is a vesicular glutamate transporter in endocrine glutamatergic systems. J Biol Chem 276:43400–43406

    Article  CAS  PubMed  Google Scholar 

  69. Winter HC, Ueda T (2008) The glutamate uptake system in synaptic vesicles: further characterization of structural requirements for inhibitors and substrates. Neurochem Res 33:223–231

    Article  CAS  PubMed  Google Scholar 

  70. 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  PubMed Central  CAS  PubMed  Google Scholar 

  71. 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 

  72. Ueda T (1986) Glutamate transport in the synaptic vesicle. In: Storm-Mathisen J, Bradford H (eds) Excitatory amino acids (Roberts PJ. Macmillan, London, pp 173–195

    Chapter  Google Scholar 

  73. Logan WJ, Snyder SH (1972) High affinity uptake systems for glycine, glutamic and aspartic acids in synaptosomes of rat central nervous tissues. Brain Res 42:413–431

    Article  CAS  PubMed  Google Scholar 

  74. Schousboe A, Hertz L (1981) Role of astroglial cells in glutamate homeostasis. In: Di Chihara G, Gressa GL (eds) Glutamate as a neurotransmitter. Raven Press, New York, pp 103–113

    Google Scholar 

  75. Ueda T (1984) ATP-dependent uptake of glutamate into synaptic vesicles. In: Oosawa F, Yoshioka T, Hayashi H (eds) Transmembrane signaling and sensation. Japan Scientific Societies Press, Tokyo, pp 247–262

    Google Scholar 

  76. Maycox PR, Hell JW, Jahn R (1990) Amino acid neurotransmission: spotlight on synaptic vesicles. Trends Neurosci 13:83–87

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  78. 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 

  79. 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Preobraschenski J, Zander JF, Suzuki T, Ahnert-Hilger G, Jahn R (2014) Vesicular glutamate transporters use flexible anion and cation binding sites for efficient accumulation of neurotransmitter. Neuron 84:1287–1301

    Article  CAS  PubMed  Google Scholar 

  81. Ni B, Rosteck PR Jr, Nadi NS, Paul SM (1994) Cloning and expression of a cDNA encoding a brain-specific Na(+)-dependent inorganic phosphate cotransporter. Proc Natl Acad Sci USA 91:5607–5611

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Aihara Y, Mashima H, Onda H, Hisano S, Kasuya H, Hori T, Yamada S, Tomura H, Yamada Y, Inoue I, Kojima I, Takeda J (2000) Molecular cloning of a novel brain-type Na+-dependent inorganic phosphate cotransporter. J Neurochem 74:2622–2625

    Article  CAS  PubMed  Google Scholar 

  83. Gras C, Herzog E, Bellenchi GC, Bernard V, Ravassard P, Pohl M, Gasnier B, Giros B, El Mestikawy S (2002) A third vesicular glutamate transporter expressed by cholinergic and serotoninergic neurons. J Neurosci 22:5442–5451

    CAS  PubMed  Google Scholar 

  84. Fremeau RT Jr, Burman J, Qureshi T, Tran CH, Proctor J, Johnson J, Zhang H, Sulzer D, Copenhagen DR, Storm-Mathisen J, Reimer RJ, Chaudhry FA, Edwards RH (2002) The identification of vesicular glutamate transporter 3 suggests novel modes of signaling by glutamate. Proc Natl Acad Sci USA 99:14488–14493

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Morimoto R, Hayashi M, Yatsushiro S, Otsuka M, Yamamoto A, Moriyama Y (2003) Co-expression of vesicular glutamate transporters (VGLUT1 and VGLUT2) and their association with synaptic-like microvesicles in rat pinealocytes. J Neurochem 84:382–391

    Article  CAS  PubMed  Google Scholar 

  86. Fremeau RT Jr, Voglmaier S, Seal RP, Edwards RH (2004) VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate. Trends Neurosci 27:98–103

    Article  CAS  PubMed  Google Scholar 

  87. 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 

  88. Herzog E, Takamori S, Jahn R, Brose N, Wojcik SM (2006) Synaptic and vesicular co-localization of the glutamate transporters VGLUT1 and VGLUT2 in the mouse hippocampus. J Neurochem 99:1011–1018

    Article  CAS  PubMed  Google Scholar 

  89. Persson S, Boulland JL, Aspling M, Larsson M, Fremeau RT Jr, Edwards RH, Storm-Mathisen J, Chaudhry FA, Broman J (2006) Distribution of vesicular glutamate transporters 1 and 2 in the rat spinal cord, with a note on the spinocervical tract. J Comp Neurol 497:683–701

    Article  CAS  PubMed  Google Scholar 

  90. Brumovsky P, Watanabe M, Hökfelt T (2007) Expression of the vesicular glutamate transporters-1 and -2 in adult mouse dorsal root ganglia and spinal cord and their regulation by nerve injury. Neurosci 147:469–490

    Article  CAS  Google Scholar 

  91. 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 

  92. Ge SN, Ma YF, Hioki H, Wei YY, Kaneko T, Mizuno N, Gao GD, Li JL (2010) Coexpression of VGLUT1 and VGLUT2 in trigeminothalamic projection neurons in the principal sensory trigeminal nucleus of the rat. J Comp Neurol 518:3149–3168

    Article  CAS  PubMed  Google Scholar 

  93. 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 USA 101:7158–7163

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  94. 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 

  95. Moechars D, Weston MC, Leo S, Callaerts-Vegh Z, Goris I, Daneels G, Buist A, Cik M, van der Spek P, Kass S, Meert T, D’Hooge R, Rosenmund C, Hampson RM (2006) Vesicular glutamate transporter VGLUT2 expression levels control quantal size and neuropathic pain. J Neurosci 26:12055–12066

    Article  CAS  PubMed  Google Scholar 

  96. Boulland JL, Qureshi T, Seal RP, Rafiki A, Gundersen V, Bergersen LH, Fremeau RT Jr, Edwards RH, Storm-Mathisen J, Chaudhry FA (2004) Expression of the vesicular glutamate transporters during development indicates the widespread corelease of multiple neurotransmitters. J Comp Neurol 480:264–280

    Article  CAS  PubMed  Google Scholar 

  97. Ni Y, Parpura V (2009) Dual regulation of Ca2+-dependent glutamate release from astrocytes: vesicular glutamate transporters and cytosolic glutamate levels. Glia 57:1296–1305

    Article  PubMed Central  PubMed  Google Scholar 

  98. Ormel L, Stensrud MJ, Chaudhry FA, Gundersen V (2012) A distinct set of synaptic-like microvesicles in atroglial cells contain VGLUT3. Glia 60:1289–1300

    Article  PubMed  Google Scholar 

  99. 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 

  100. Herman MA, Ackermann F, Trimbuch T, Rosenmund C (2014) Vesicular glutamate transporter expression level affects synaptic vesicle release probability at hippocampal synapses in culture. J Neurosci 34:11781–11791

    Article  CAS  PubMed  Google Scholar 

  101. El Mestikawy S, Wallén-Mackenzie A, Fortin GM, Descarries L, Trudeau LE (2011) From glutamate co-release to vesicular synergy: vesicular glutamate transporters. Nat Rev Neurosci 12:204–216

    Article  PubMed  CAS  Google Scholar 

  102. Cox DW, Bachelard HS (1982) Attenuation of evoked field potentials from dentate granule cells by low glucose, pyruvate + malate, and sodium fluoride. Brain Res 239:527–534

    Article  CAS  PubMed  Google Scholar 

  103. Cox DW, Morris PG, Feeney J, Bachelard HS (1983) 31Pn. m.r. studies on cerebral energy metabolism under conditions of hypoglycaemia and hypoxia in vitro. Biochem J 212:365–370

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Bachelard HS, Cox DW, Drower J (1984) Sensitivity of guinea-pig hippocampal granule cell field potentials to hexoses in vitro: an effect on cell excitability? J Physiol 352:91–102

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  105. Fleck MW, Henze DA, Barrionuevo G, Palmer AM (1993) Aspartate and glutamate mediate excitatory synaptic transmission in area CA1 of the hippocampus. J Neurosci 13:3944–3955

    CAS  PubMed  Google Scholar 

  106. Ikemoto A, Bole DG, Ueda T (2003) Glycolysis and glutamate accumulation into synaptic vesicles. Role of glyceraldehyde phosphate dehydrogenase and 3-phosphoglycerate kinase. J Biol Chem 278:5929–5940

    Article  CAS  PubMed  Google Scholar 

  107. Shepherd GMG, Harris KM (1998) Three-dimensional structure and composition of CA3-CA1 axons in rat hippocampal slices: implications for presynaptic connectivity and compartmentalization. J Neurosci 18:8300–8310

    CAS  PubMed  Google Scholar 

  108. Coughenour HD, Spaulding RS, Thompson CM (2004) The synaptic vesicle proteome: a comparative study in membrane protein identification. Proteomics 4:3141–3155

    Article  CAS  PubMed  Google Scholar 

  109. Takamori S, Holt M, Stenius K, Lemke EA, Grønborg M, Riedel D, Urlaub H, Schenck S, Brügger B, Ringler P, Müller SA, Rammner B, Gräter F, Hub JS, De Groot BL, Mieskes G, Moriyama Y, Klingauf J, Grubmüller H, Heuser J, Wieland F, Jahn R (2006) molecular anatomy of a trafficking organelle. Cell 127:831–846

    Article  CAS  PubMed  Google Scholar 

  110. Burre J, Beckhaus T, Schägger H, Corvey C, Hofmann S, Karas M, Zimmermann H, Volknandt W (2006) Analysis of the synaptic vesicle proteome using three gel-based protein separation techniques. Proteomics 6:6250–6262

    Article  CAS  PubMed  Google Scholar 

  111. Ishida A, Noda Y, Ueda T (2009) Synaptic vesicle-bound pyruvate kinase can support vesicular glutamate uptake. Neurochem Res 34:807–818

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  112. Ueda T, Ikemoto A (2007) Cytoplasmic glycolytic enzymes. Synaptic vesicle-associated glycolytic ATP-generating enzymes: coupling to neurotransmitter accumulation. In: Gibson G, Dienel G (eds) Handbook neurochem. molecular neurobiology, 3rd edn, Brain energetics, cellular and molecular integration. Springer, Heidelberg, pp 241–259

  113. Zala D, Hinckelmann MV, Yu H, Lyra da Cunha MM, Liot G, Cordelières FP, Marco S, Saudou F (2013) Vesicular glycolysis provides on-board energy for fast axonal transport. Cell 152:479–491

    Article  CAS  PubMed  Google Scholar 

  114. Bradford HF, Ward HK, Thomas AJ (1978) Glutamine—a major substrate for nerve endings. J Neurochem 30:1453–1459

    Article  CAS  PubMed  Google Scholar 

  115. Martinez-Hernandez A, Bell KP, Norenberg MD (1977) Glutamine synthetase: glial localization in brain. Science 195:1356–1358

    Article  CAS  PubMed  Google Scholar 

  116. Bradford HF, Ward HK (1976) On glutaminase activity in mammalian synaptosomes. Brain Res 110:115–125

    Article  CAS  PubMed  Google Scholar 

  117. van den Berg CJ, Garfinkel D (1971) A simulation study of brain compartments. Metabolism of glutamate and related substances in mouse brain. Biochem J 123:211–218

    Article  PubMed  Google Scholar 

  118. Benjamin AM, Quastel JH (1972) Locations of amino acids in brain slices from the rat. Biochem J 128:631–646

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  119. Cotman CW, Foster AC, Lanthorn TH (1981) An overview of glutamate as a neurotransmitter. In: Di Chiara G, Gessa GL (eds) Glutamate as a neurotransmitter. Raven Press, New York, pp 1–27

    Google Scholar 

  120. Shank RP, Aprison MH (1988) Glutamate as a neurotransmitter. In: Kvamme E (ed) Glutamine and glutamate in mammals, vol. II. CRC Press, Boca Raton, pp 3–20

    Google Scholar 

  121. Schousboe A, Westergaard N, Waagepetersen H, Larsson OM, Bakken IJ, Sonnewald U (1997) Trafficking between glia and neurons of TCA cycle intermediates and related metabolites. Glia 21:99–105

    Article  CAS  PubMed  Google Scholar 

  122. Kvamme E, Torgner IA, Roberg B (1991) Evidence indicating that pig renal phosphate-activated glutaminase has a functionally predominant external localization in the inner mitochondrial membrane. J Biol Chem 266:13185–13192

    CAS  PubMed  Google Scholar 

  123. Roberg B, Torgner IA, Kvamme E (1995) The orientation of phosphate activated glutaminase in the inner mitochondrial membrane of synaptic and non-synaptic rat brain mitochondria. Neurochem Int 27:367–376

    Article  CAS  PubMed  Google Scholar 

  124. Shapiro RA, Haser WG, Curthoys NP (1985) The orientation of phosphate-dependent glutaminase on the inner membrane of rat renal mitochondria. Arch Biochem Biophys 243:1–7

    Article  CAS  PubMed  Google Scholar 

  125. Aledo JC, de Pedro E, Gomez-Fabre PM, de Castro IN, Marquez J (1997) Submitochondrial localization and membrane topography of Ehrlich ascitic tumour cell glutaminase. Biochim Biophys Acta 1323:173–184

    Article  CAS  PubMed  Google Scholar 

  126. Albrecht J, Dolinska M, Hilgier W, Lipkowski AW, Nowacki J (2000) Modulation of glutamine uptake and phosphate-activated glutaminase activity in rat brain mitochondria by amino acids and their synthetic analogues. Neurochem Int 36:341–347

    Article  CAS  PubMed  Google Scholar 

  127. Ziemińska E, Hilgier W, Waagepetersen HS, Hertz L, Sonnewald U, Schousboe A, Albrecht J (2004) Analysis of glutamine accumulation in rat brain mitochondria in the presence of a glutamine uptake inhibitor, histidine, reveals glutamine pools with a distinct access to deamidation. Neurochem Res 29:2121–2123

    Article  PubMed  Google Scholar 

  128. Bak LK, Zieminnska E, Waagepetersen HS, Schousboe A, Albrecht J (2008) Metabolism of [U-13C] glutamine and [U-13C]glutamate in isolated rat brain mitochondria suggests functional phosphate-activated glutaminase activity in matrix. Neurochem Res 33:273–278

    Article  CAS  PubMed  Google Scholar 

  129. Palaiologos G, Hertz L, Schousboe A (1988) Evidence that aspartate aminotransferase activity and ketodicarboxylate carrier function are essential for biosynthesis of transmitter glutamate. J Neurochem 51:317–320

    Article  CAS  PubMed  Google Scholar 

  130. Dennis SC, Lai JC, Clark JB (1977) Comparative studies on glutamate metabolism in synpatic and non-synaptic rat brain mitochondria. Biochem J 164:727–736

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  131. Bisaccia F, Indiveri C, Palmieri F (1985) Purification of reconstitutively active alpha-oxoglutarate carrier from pig heart mitochondria. Biochim Biophys Acta 810:362–369

    Article  CAS  PubMed  Google Scholar 

  132. Bolli R, Nałecz KA, Azzi A (1989) Monocarboxylate and alpha-ketoglutarate carriers from bovine heart mitochondria. Purification by affinity chromatography on immobilized 2-cyano-4-hydroxycinnamate. J Biol Chem 264:18024–18030

    CAS  PubMed  Google Scholar 

  133. Schousboe A, Bak LK, Waagepetersen HS (2013) Astrocytic control of biosynthesis and turnover of the neurotransmitters glutamate and GABA. Front Endocrinol (Lausanne) 4:102

    Google Scholar 

  134. Takeda K, Ishida A, Takahashi K, Ueda T (2012) Synaptic vesicles are capable of synthesizing the VGLUT substrate glutamate from α-ketoglutarate for vesicular loading. J Neurochem 121:184–196

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  135. Westergaard N, Sonnewald U, Schousboe A (1994) Release of α-ketoglutarate, malate and succinate from cultured astrocytes: possible role in amino acid neurotransmitter homeostasis. Neurosci Lett 176:105–109

    Article  CAS  PubMed  Google Scholar 

  136. Patel MS (1974) The relative significance of CO -fixing enzymes in the metabolism of rat brain. J Neurochem 22:717–724

    Article  CAS  PubMed  Google Scholar 

  137. Yu AC, Drejer J, Hertz L, Schousboe A (1983) Pyruvate carboxylase activity in primary cultures of astrocytes and neurons. J Neurochem 41:1484–1487

    Article  CAS  PubMed  Google Scholar 

  138. Shank RP, Bennett GS, Freytag SO, Campbell GL (1985) Pyruvate carboxylase: astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools. Brain Res 329:364–367

    Article  CAS  PubMed  Google Scholar 

  139. Shank RP, Leo GC, Zielke HR (1993) Cerebral metabolic compartmentation as revealed by nuclear magnetic resonance analysis of D-[1-13C]glucose metabolism. J Neurochem 61:315–323

    Article  CAS  PubMed  Google Scholar 

  140. Cesar M, Hamprecht B (1995) Immunocytochemical examination of neural rat and mouse primary cultures using monoclonal antibodies raised against pyruvate carboxylase. J Neurochem 64:2312–2318

    Article  CAS  PubMed  Google Scholar 

  141. Hertz L, Peng L, Dienel GA (2007) Energy metabolism in astrocytes: high rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogenolysis. J Cereb Blood Flow Metab 27:219–249

    Article  CAS  PubMed  Google Scholar 

  142. Serres S, Raffard G, Franconi JM, Merle M (2008) Close coupling between astrocytic and neuronal metabolisms to fulfill anaplerotic and energy needs in the rat brain. J Cereb Blood Flow Metab 28:712–724

    Article  CAS  PubMed  Google Scholar 

  143. Sonnewald U, Rae C (2010) Pyruvate carboxylation in different model systems studied by 13C MRS. Neurochem Res 35:1916–1921

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  144. Morken TS, Brekke E, Håberg A, Widerøe M, Brubakk AM, Sonnewald U (2014) Neuron–astrocyte interactions, pyruvate carboxylation and the pentose phosphate pathway in the neonatal rat brain. Neurochem Res 39:556–569

    Article  CAS  PubMed  Google Scholar 

  145. Sonnewald U (2014) Glutamate synthesis has to be matched by its degradation—where do all the carbons go? J Neurochem 131:399–406

    Article  CAS  PubMed  Google Scholar 

  146. Shank RP, LeM Campbell G (1981) Avid Na+-dependent high-affinity uptake of alpha-ketoglutarate by nerve terminal enriched material from mouse cerebellum. Life Sci 28:843–850

    Article  CAS  PubMed  Google Scholar 

  147. Shank RP, Campbell GL (1982) Glutamine and alpha-ketoglutarate uptake and metabolism by nerve terminals enriched material from mouse cerebellum. Neurochem Res 7:601–616

    Article  CAS  PubMed  Google Scholar 

  148. Shank RP, Campbell GL (1984) Alpha-ketoglutarate and malate uptake and metabolism by synaptosomes: further evidence for an astrocyte-to-neuron metabolic shuttle. J Neurochem 42:1153–1161

    Article  CAS  PubMed  Google Scholar 

  149. Tildon JT, Roeder LM, Stevenson JH (1985) Substrate oxidation by isolated rat brain mitochondria and synaptosomes. J Neurosci Res 14:207–215

    Article  CAS  PubMed  Google Scholar 

  150. 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

    Article  CAS  PubMed  Google Scholar 

  151. McKenna MC, Stevenson JH, Huan X, Hopkins IB (2000) Differential distribution of the enzymes glutamate dehydrogenase and aspartate aminotransferase in cortical synaptic mitochondria contributes to metabolic compartmentation in cortical synaptic terminals. Neurochem Int 37:229–241

    Article  CAS  PubMed  Google Scholar 

  152. McKenna MC (2007) The glutamate–glutamine cycle is not stoichiometric: fates of glutamate in brain. J Neurosci Res 85:3347–3358

    Article  CAS  PubMed  Google Scholar 

  153. Altschuler RA, Neises GR, Harmison GG, Wenthold RJ, Fex J (1981) Immunocytochemical localization of aspartate aminotransferase immunoreactivity in cochlear nucleus of the guinea pig. Proc Natl Acad Sci USA 78:6553–6657

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  154. Altschuler RA, Mosinger JL, Harmison GG, Parakkal MH, Wenthold RJ (1982) Aspartate aminotransferase-like immunoreactivity as a marker for aspartate/glutamate in guinea pig photoreceptors. Nature 298:657–659

    Article  CAS  PubMed  Google Scholar 

  155. Kam K, Nicoll R (2007) Excitatory synaptic transmission persists independently of the glutamate–glutamine cycle. J Neurosci 27:9192–9200

    Article  CAS  PubMed  Google Scholar 

  156. Masson J, Darmon M, Conjard A, Chuhma N, Ropert N, Thoby-Brisson M, Foutz AS, Parrot S, Miller GM, Jorisch R, Polan J, Hamon M, Hen R, Rayport S (2006) Mice lacking brain/kidney phosphate-activated glutaminase have impaired glutamatergic synaptic transmission, altered breathing, disorganized goal-directed behavior and die shortly after birth. J Neurosci 26:4660–4671

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  157. Carlson MD, Kish PE, Ueda T (1989) Glutamate uptake into synaptic vesicles: competitive inhibition by bromocriptine. J Neurochem 53:1889–1994

    Article  CAS  PubMed  Google Scholar 

  158. Winter HC, Ueda T (1993) Glutamate uptake system in the presynapric vesicle: glutamic acid analogs as inhibitors and alternative substrates. Neurochem Res 18:79–85

    Article  CAS  PubMed  Google Scholar 

  159. Roseth S, Fykse EM, Fonnum F (1995) Uptake of l-glutamate into rat brain synaptic vesicles: effect of inhibitors that bind specifically to the glutamate transporter. J Neurochem 65:96–103

    Article  CAS  PubMed  Google Scholar 

  160. Ozkan ED, Lee FS, Ueda T (1997) A protein factor that inhibits ATP-dependent glutamate and gamma-aminobutyric acid accumulation into synaptic vesicles: purification and initial characterization. Proc Natl Acad Sci USA 94:4137–4142

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  161. Roseth S, Fykse EM, Fonnum F (1998) Uptake of l-glutamate into synaptic vesicles: competitive inhibition by dyes with biphenyl and amino and sulphonic acid substituted naphthyl groups. Biochem Pharmacol 56:1243–1249

    Article  CAS  PubMed  Google Scholar 

  162. Fonnum F, Fykse EM, Roseth S (1998) Uptake of glutamate into synaptic vesicles. Prog Brain Res 116:87–101

    Article  CAS  PubMed  Google Scholar 

  163. Bartlett RD, Esslinger CS, Thompson CM, Bridges RJ (1998) Substituted quinolines as inhibitors of l-glutamate transport into synaptic vesicles. Neuropharmacology 37:839–846

    Article  CAS  PubMed  Google Scholar 

  164. Tamura Y, Ozkan ED, Bole DG, Ueda T (2001) IPF, a vesicular uptake inhibitory protein factor, can reduce the Ca2+-dependent, evoked release of glutamate, GABA and serotonin. J Neurochem 76:1153–1164

    Article  CAS  PubMed  Google Scholar 

  165. Ogita K, Hirata K, Bole DG, Yoshida S, Tamura Y, Leckenby AM, Ueda T (2001) Inhibition of vesicular glutamate storage and exocytotic release by Rose Bengal. J Neurochem 77:34–42

    Article  CAS  PubMed  Google Scholar 

  166. Carrigan CN, Bartlett RD, Esslinger CS, Cybulski KA, Tongcharoensirikul P, Bridges RJ, Thompson CM (2002) Synthesis and in vitro pharmacology of substituted quinoline-2,4-dicarboxylic acids as inhibitors of vesicular glutamate transport. J Med Chem 45:2260–2276

    Article  CAS  PubMed  Google Scholar 

  167. Bole DG, Ueda T (2005) Inhibition of vesicular uptake by Rose Bengal-related compounds: structure activity relationship. Neurochem Res 30:363–369

    Article  CAS  PubMed  Google Scholar 

  168. Thompson CM, Davis E, Carrigan CN, Cox HD, Bridges RJ, Gerdes JM (2005) Inhibitors of the glutamate vesicular transporter (VGLUT). Curr Med Chem 12:2041–2056

    Article  CAS  PubMed  Google Scholar 

  169. Patel SA, Nagy JO, Bolstad ED, Gerdes JM, Thompson CM (2007) Tetrapeptide inhibitors of the glutamate vesicular transporter (VGLUT). Bioorg Med Chem Lett 17:5125–5128

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  170. Winter HC, Ueda T (2008) The glutamate uptake system in presynaptic vesicles: further characterization of structural requirements for inhibitors and substrates. Neurochem Res 33:223–231

    Article  CAS  PubMed  Google Scholar 

  171. Pietrancosta N, Kessler A, Favre-Besse FC, Triballeau N, Quentin T, Giros B, El Mestikawy S, Acher FC (2010) Rose Bengal analogs and vesicular glutamate transporters (VGLUTs). Bioorg Med Chem 18:6922–6933

    Article  CAS  PubMed  Google Scholar 

  172. Tamura Y, Ogita K, Ueda T (2014) A new VGLUT-specific potent inhibitor: pharmacophore of brilliant yellow. Neurochem Res 39:117–128

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  173. Neale SA, Copeland CS, Uebele VN, Thomson FJ, Salt TE (2013) Modulation of hippocampal synaptic transmission by the kynurenine pathway member xanthurenic acid and other VGLUT inhibitors. Neuropsychopharmacology 38:1060–1067

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  174. Neale SA, Copeland CS, Salt TE (2014) Effect of VGLUT inhibitors on glutamatergic synaptic transmission in the rodent hippocampus and prefrontal cortex. Neurochem Int 73:159–165

    Article  CAS  PubMed  Google Scholar 

  175. Reis M, Farage M, Wolosker H (2000) Chloride-dependent inhibition of vesicular glutamate uptake by alpha-keto acids accumulated in maple syrup urine disease. Biochim Biophys Acta 1475:114–118

    Article  CAS  PubMed  Google Scholar 

  176. Di Cosmo A, Nardi G, Di Cristo C, De Santis A, Messenger JB (1999) Localization of l-glutamate and glutamate-like receptors at the squid giant synapse. Brain Res 839:213–220

    Article  PubMed  Google Scholar 

  177. Kawagoe R, Onodera K, Takeuchi A (1984) The uptake and release of glutamate at the crayfish neuromuscular junction. J Physiol 354:69–78

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  178. Katz B, Miledi R (1965) The effect of calcium on acetylcholine release from motor nerve terminals. Proc R Soc Lond B Biol Sci 161:496–503

    Article  CAS  PubMed  Google Scholar 

  179. Katz B, Miledi R (1967) The timing of calcium action during neuromuscular transmission. J Physiol 189:535–544

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  180. Katz B, Miledi R (1967) A study of synaptic transmission in the absence of nerve impulses. J Physiol 192:407–436

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  181. Katz B, Miledi R (1970) Further study of the role of calcium in synaptic transmission. J Physiol 207:789–801

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  182. Llinas R, Nicholson C (1975) Calcium role in depolarization-secretion coupling: and aequorin study in squid giant synapse. Proc Natl Acad Sci USA 72:187–190

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  183. Llinas R, Steinberg IZ, Walton K (1976) Presynaptic calcium currents and their relation to synaptic transmission: voltage clamp study in squid giant synapse and theoretical model for the calcium gate. Proc Natl Acad Sci USA 73:2918–2922

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  184. Nowycky MC, Fox AP, Tsien RW (1985) Three types of neuronal calcium channel with different calcium agonist sensitivity. Nature 316:440–443

    Article  CAS  PubMed  Google Scholar 

  185. Fox AP, Nowycky MC, Tsien RW (1987) Kinetic and pharmacological properties distinguishing three types of calcium currents in chick sensory neurones. J Physiol 394:149–172

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  186. Hirning LD, Fox AP, McCleskey EW, Olivera BM, Thayer SA, Miller RJ, Tsien RW (1988) Dominant role of N-type Ca2+ channels in evoked release of norepinephrine from sympathetic neurons. Science 239:57–61

    Article  CAS  PubMed  Google Scholar 

  187. Catterall WA, Few AP (2008) Calcium channel regulation and presynaptic plasticity. Neuron 59:882–901

    Article  CAS  PubMed  Google Scholar 

  188. Luebke JI, Dunlap K, Turner TJ (1993) Multiple calcium channel types control glutamatergic synaptic transmission in the hippocampus. Neuron 11:895–902

    Article  CAS  PubMed  Google Scholar 

  189. Wheeler DB, Randall A, Tsien RW (1994) Roles of N-type and Q-type Ca2+ channels in supporting hippocampal synaptic transmission. Science 264:107–111

    Article  CAS  PubMed  Google Scholar 

  190. Charlton MP, Augustine GJ (1990) Classification of presynaptic calcium channels at the squid giant synapse: neither T-, L- nor N-type. Brain Res 525:133–139

    Article  CAS  PubMed  Google Scholar 

  191. Araque A, Clarac F, Buno W (1994) P-type Ca2 + channels mediate excitatory and inhibitory synaptic transmitter release in crayfish muscle. Proc Natl Acad Sci USA 91:4224–4228

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  192. Quastel DMJ, Hackett JT, Cooke JD (1971) Calcium: is it required for transmitter secretion? Science 172:1034–1036

    Article  CAS  PubMed  Google Scholar 

  193. Brosius DC, Hackett JT, Tuttle JB (1992) Ca(2 +)-independent and Ca(2 +)-dependent stimulation of quantal neurosecretion in avian ciliary ganglion neurons. J Neurophysiol 68:1229–1234

    CAS  PubMed  Google Scholar 

  194. Sudhof TC (2013) Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron 80:675–690

    Article  CAS  PubMed  Google Scholar 

  195. Geppert M, Goda Y, Hammer RE, Li C, Rosahl TW, Stevens CF, Sudhof TC (1994) Synaptotagmin I: a major Ca2 + sensor for transmitter release at a central synapse. Cell 79:717–727

    Article  CAS  PubMed  Google Scholar 

  196. Fernandez-Chacon R, Konigstorfer A, Gerber SH, Garcia J, Matos MF, Stevens CF, Brose N, Rizo J, Rosenmund C, Sudhof TC (2001) Synaptotagmin I functions as a calcium regulator of release probability. Nature 410:41–49

    Article  CAS  PubMed  Google Scholar 

  197. Sudhof TC, Rothman JE (2009) Membrane fusion: grappling with SNARE and SM proteins. Science 323:474–477

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  198. Sudhof TC (2013) A molecular machine for neurotransmitter release: synaptotagmin and beyond. Nat Med 19:1227–1231

    Article  PubMed  CAS  Google Scholar 

  199. Sudhof TC (2013) Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron 89:675–690

    Article  CAS  Google Scholar 

  200. Greengard P, Valtorta F, Czernik AJ, Benfenati F (1993) Synaptic vesicle phosphoproteins and regulation of synaptic function. Science 259:780–785

    Article  CAS  PubMed  Google Scholar 

  201. Llinas R, McGuinness TL, Leonard CS, Sugimori M, Greengard P (1985) Intraterminal injection of Synapsin I or calcium/calmodulin-dependent protein kinase II alters neurotransmitter release at the squid giant synapse. Proc Natl Acad Sci USA 82:3035–3039

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  202. Hackett JT, Cochran SL, Greenfield LJ Jr, Brosius DC, Ueda T (1990) Synapsin I injected presynaptically into goldfish mauthner axons reduces quantal synaptic transmission. J Neurophysiol 63:701–706

    CAS  PubMed  Google Scholar 

  203. Tokumaru H, Umayahara K, Pellegrini LL, Ishizuka T, Saisu H, Betz H, Augustine GJ, Abe T (2001) SNARE complex oligomerization by synaphin/complexin is essential for synaptic vesicle exocytosis. Cell 104:421–432

    Article  CAS  PubMed  Google Scholar 

  204. Steyer JA, Horstmann H, Almers W (1997) Transport, docking and exocytosis of single secretory granules in live chromaffin cells. Nature 388:474–478

    Article  CAS  PubMed  Google Scholar 

  205. Zenisek D, Steyer JA, Feldman ME, Almers W (2002) A membrane marker leaves synaptic vesicles in milliseconds after exocytosis in retinal bipolar cells. Neuron 35:1085–1097

    Article  CAS  PubMed  Google Scholar 

  206. Mallart A, Martin AR (1967) An analysis of facilitation of transmitter release at the neuromuscular junction of the frog. J Physiol 193:679–694

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  207. Charlton MP, Bittner GD (1978) Facilitation of transmitter release at squid synapses. J Gen Physiol 72:471–486

    Article  CAS  PubMed  Google Scholar 

  208. Dudel J, Kuffler SW (1981) Mechanism of facilitation at the crayfish neuromuscular junction. J Physiol 155:530–542

    Article  Google Scholar 

  209. Wernig A (1972) Changes in statistical parameters during facilitation at the crayfish neuromuscular junction. J Physiol 226:751–759

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  210. Linder TM (1974) The accumulative properties of facilitation at crayfish neuromuscular synapses. J Physiol 238:223–234

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  211. Herman MA, Ackermann F, Trimbuch T, Rosenmund C (2014) Vesicular glutamate transporter expression level affects synaptic vesicle release probability at hippocampal synapses in culture. J Neurosci 34:11781–11791

    Article  CAS  PubMed  Google Scholar 

  212. Worden MK, Bykhovskaia M, Hackett JT (1997) Facilitation at the lobster neuromuscular junction: a stimulus-dependent mobilization model. J Neurophysiol 78:417–428

    CAS  PubMed  Google Scholar 

  213. Bykhovskaia M, Hackett JT, Worden MK (1999) Asynchrony of quantal events in evoked multiquantal responses indicates presynaptic quantal interaction. J Neurophysiol 81:2234–2242

    CAS  PubMed  Google Scholar 

  214. Katz B, Miledi R (1968) Further studies on the role of calcium in synaptic transmission. J Physiol 207:789–801

    Article  Google Scholar 

  215. Kamiya H, Zucker RS (1994) Residual Ca2+ and short-term synaptic plasticity. Nature 371:603–606

    Article  CAS  PubMed  Google Scholar 

  216. Magleby KL (1979) Facilitation, augmentation, and potentiation of transmitter release. Prog Brain Res 49:175–182

    Article  CAS  PubMed  Google Scholar 

  217. Dixon D, Atwood HL (1989) Conjoint action of phosphatidylinositol and adenylate cyclase systems in serotonin-induced facilitation at the crayfish neuromuscular junction. J Neurophysiol 62:1251–1259

    CAS  PubMed  Google Scholar 

  218. Bliss TV, Lomo T (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 232:331–356

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  219. Granger AJ, Nicoll RA (2014) Expression mechanisms underlying long-term potentiation: a postsynaptic view, 10 years on. Philos Trans R Soc Lond B Biol Sci 369:20130136

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  220. Hamilton NB, Attwell D (2010) Do astrocytes really exocytose neurotransmitters? Nat Rev Neurosci 11:227–238

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tetsufumi Ueda.

Additional information

Special Issue: In Honor of Dr. Gerald Dienel.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hackett, J.T., Ueda, T. Glutamate Release. Neurochem Res 40, 2443–2460 (2015). https://doi.org/10.1007/s11064-015-1622-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-015-1622-1

Keywords

Navigation