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Neurotransmitters and Integration in Neuronal-Astroglial Networks

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Abstract

Two major neural cell types, glia, astrocytes in particular, and neurones can release chemical transmitters that act as soluble signalling compounds for intercellular communication. Exocytosis, a process which depends on an increase in cytosolic Ca2+ levels, represents a common denominator for release of neurotransmitters, stored in secretory vesicles, from these neural cells. While neurones rely predominately on the immediate entry of Ca2+ from the extracellular space to the cytosol in this process, astrocytes support their cytosolic Ca2+ increases by appropriating this ion from the intracellular endoplasmic reticulum store and extracellular space. Additionally, astrocytes can release neurotransmitters using a variety of non-vesicular pathways which are mediated by an assortment of plasmalemmal channels and transporters. Once a neuronal and/or astrocytic neurotransmitter is released into the extracellular space, it can activate plasma membrane neurotransmitter receptors on neural cells, causing autocrine and/or paracrine signalling. Moreover, chemical transmission is essential not only for homocellular, but also for heterocellular bi-directional communication in the brain. Further detailed understanding of chemical transmission will aid our comprehension of the brain (dys)function in heath and disease.

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References

  1. Du Bois-Reymond E (1877) Gesammelte Abhandlungen zur Allgemeinen Muskel-und Nervenphysik. Veit & Co., Leipzig

    Google Scholar 

  2. Lopez-Munoz F, Alamo C (2009) Historical evolution of the neurotransmission concept. J Neural Trans 116:515–533

    Article  CAS  Google Scholar 

  3. Descartes R (1664) L’Homme, et un traité de la formation du foetus du mesme autheur. Avec les remarques de Louys de La Forge, 1st edn. Nicolas Le Gras, Paris, pp 1–449

  4. Elliott TR (1904) On the action of adrenaline. J Physiol Lond 31:xx–xxi

    Google Scholar 

  5. Langley JN (1905) On the reactions of cells and nerve-endings to certain poisons, chiefly as regards the reaction of striated muscle to nicotine and curari. J Physiol Lond 33:374–413

    PubMed  Google Scholar 

  6. Langley JN (1906) On nerve endings and on special excitable substances in cells. Proc R Soc Lond 78:170–194

    Article  CAS  Google Scholar 

  7. Dale HH (1914) The action of certain esters and ethers of choline, and their relation to muscarine. J Pharmacol 6:147–190

    CAS  Google Scholar 

  8. Loewi O (1921) Über humorale Übertragbarkeit der Herznervenwirkung. Pflügers Arch 189:239–242

    Article  Google Scholar 

  9. Von Euler US (1946) A specific sympathomimetic ergone in adrenergic nerve fibres (sympathin) and its relations to adrenaline and nor-adrenaline. Acta Physiol Scand 12:73–97

    Article  Google Scholar 

  10. Eccles JC (1964) The physiology of synapses. Springer, Berlin

    Book  Google Scholar 

  11. Burnstock G (1972) Purinergic nerves. Pharmacol Rev 24:509–581

    PubMed  CAS  Google Scholar 

  12. Eccles J (1976) From electrical to chemical transmission in the central nervous system. Notes Rec R Soc Lond 30:219–230

    Article  PubMed  CAS  Google Scholar 

  13. Burnstock G (1976) Do some nerve cells release more than one transmitter? Neuroscience 1:239–248

    Article  PubMed  CAS  Google Scholar 

  14. Del Castillo J, Katz B (1954) Quantal components of the end-plate potential. J Physiol 124:560–573

    Google Scholar 

  15. Fatt P, Katz B (1952) Spontaneous subthreshold activity at motor nerve endings. J Physiol 117:109–128

    PubMed  CAS  Google Scholar 

  16. Sollner T, Whiteheart SW, Brunner M, Erdjument-Bromage H, Geromanos S, Tempst P, Rothman JE (1993) SNAP receptors implicated in vesicle targeting and fusion. Nature 362:318–324

    Article  PubMed  CAS  Google Scholar 

  17. Sudhof TC, De Camilli P, Niemann H, Jahn R (1993) Membrane fusion machinery: insights from synaptic proteins. Cell 75:1–4

    PubMed  CAS  Google Scholar 

  18. de Wit H, Walter AM, Milosevic I, Gulyas-Kovacs A, Riedel D, Sorensen JB, Verhage M (2009) Synaptotagmin-1 docks secretory vesicles to syntaxin-1/SNAP-25 acceptor complexes. Cell 138:935–946

    Article  PubMed  CAS  Google Scholar 

  19. Jorgacevski J, Potokar M, Grilc S, Kreft M, Liu W, Barclay JW, Buckers J, Medda R, Hell SW, Parpura V, Burgoyne RD, Zorec R (2011) Munc18-1 tuning of vesicle merger and fusion pore properties. J Neurosci 31:9055–9066

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  21. Toonen RF, Verhage M (2007) Munc18-1 in secretion: lonely Munc joins SNARE team and takes control. Trends Neurosci 30:564–572

    Article  PubMed  CAS  Google Scholar 

  22. Verhage M, Sorensen JB (2008) Vesicle docking in regulated exocytosis. Traffic 9:1414–1424

    Article  PubMed  CAS  Google Scholar 

  23. Weninger K, Bowen ME, Choi UB, Chu S, Brunger AT (2008) Accessory proteins stabilize the acceptor complex for synaptobrevin, the 1:1 syntaxin/SNAP-25 complex. Structure 16:308–320

    Article  PubMed  CAS  Google Scholar 

  24. Weninger K, Bowen ME, Chu S, Brunger AT (2003) Single-molecule studies of SNARE complex assembly reveal parallel and antiparallel configurations. Proc Natl Acad Sci USA 100:14800–14805

    Article  PubMed  CAS  Google Scholar 

  25. Zilly FE, Sorensen JB, Jahn R, Lang T (2006) Munc18-bound syntaxin readily forms SNARE complexes with synaptobrevin in native plasma membranes. PLoS Biol 4:e330

    Article  PubMed  CAS  Google Scholar 

  26. Parpura V, Baker BJ, Jeras M, Zorec R (2010) Regulated exocytosis in astrocytic signal integration. Neurochem Int 57:451–459

    Article  PubMed  CAS  Google Scholar 

  27. Sudhof TC (2004) The synaptic vesicle cycle. Annu Rev Neurosci 27:509–547

    Article  PubMed  CAS  Google Scholar 

  28. Tucker WC, Chapman ER (2002) Role of synaptotagmin in Ca2+-triggered exocytosis. Biochem J 366:1–13

    PubMed  CAS  Google Scholar 

  29. Tucker WC, Weber T, Chapman ER (2004) Reconstitution of Ca2+-regulated membrane fusion by synaptotagmin and SNAREs. Science 304:435–438

    Article  PubMed  CAS  Google Scholar 

  30. Locke FS (1894) Notiz uber den Einfluss, physiologisher Kochsalzlosung auf die Eregbarkeit von Muscel and Nerve. Zentralbl Physiol 8:166–167

    Google Scholar 

  31. Overton E (1904) Beitrage zur allgemeinen Muskel- und Nerven physiologie. III. Mittheilung. Studien uber die Wirkung der Alkali- und Erdkali-salze auf Skeletalmuskeln und Nerven. Pflugers Arch 105:176–290

    Article  CAS  Google Scholar 

  32. 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  PubMed  CAS  Google Scholar 

  33. Katz B, Miledi R (1967) Ionic requirements of synaptic transmitter release. Nature 215:651

    Article  PubMed  CAS  Google Scholar 

  34. Takahashi T (2005) Dynamic aspects of presynaptic calcium currents mediating synaptic transmission. Cell Calcium 37:507–511

    Article  PubMed  CAS  Google Scholar 

  35. Wang Z, Chapman ER (2010) Rat and Drosophila synaptotagmin 4 have opposite effects during SNARE-catalyzed membrane fusion. J Biol Chem 285:30759–30766

    Article  PubMed  CAS  Google Scholar 

  36. Parpura V, Zorec R (2010) Gliotransmission: Exocytotic release from astrocytes. Brain Res Rev 63:83–92

    Article  PubMed  CAS  Google Scholar 

  37. Parpura V, Heneka MT, Montana V, Oliet SH, Schousboe A, Haydon PG, Stout RF Jr, Spray DC, Reichenbach A, Pannicke T, Pekny M, Pekna M, Zorec R, Verkhratsky A (2012) Glial cells in (patho)physiology. J Neurochem 121:4–27

    Article  PubMed  CAS  Google Scholar 

  38. Verkhratsky A, Parpura V, Rodriguez JJ (2011) Where the thoughts dwell: the physiology of neuronal-glial “diffuse neural net”. Brain Res Rev 66:133–151

    Article  PubMed  Google Scholar 

  39. Held H (1909) Über die Neuroglia marginalis der menschlichen Grosshirnrinde. Monatschr. f Psychol u Neurol. 26 Rdg.-Heft: 360-416

  40. Glees P (1955) Neuroglia morphology and function. Blackwell, Oxford

    Google Scholar 

  41. Nageotte J (1910) Phenomenes de secretion dans le protoplasma des cellules nevrogliques de la substance grise. C R Soc Biol (Paris) 68:1068–1069

    Google Scholar 

  42. Bowery NG, Brown DA, Collins GG, Galvan M, Marsh S, Yamini G (1976) Indirect effects of amino-acids on sympathetic ganglion cells mediated through the release of gamma-aminobutyric acid from glial cells. Br J Pharmacol 57:73–91

    Article  PubMed  CAS  Google Scholar 

  43. Malarkey EB, Parpura V (2009) Mechanisms of transmitter release from astrocytes. In: Parpura V, Haydon PG (eds) Astrocytes in (patho)physiology of the nervous system. In: Astrocytes in (patho)physiology of the nervous system. Springer, New York, pp 301–350

  44. Ni Y, Malarkey EB, Parpura V (2007) Vesicular release of glutamate mediates bidirectional signaling between astrocytes and neurons. J Neurochem 103:1273–1284

    Article  PubMed  CAS  Google Scholar 

  45. Parpura V, Verkhratsky A (2012) The astrocyte excitability brief: From receptors to gliotransmission. Neurochem Int (in press)

  46. Sawada K, Echigo N, Juge N, Miyaji T, Otsuka M, Omote H, Yamamoto A, Moriyama Y (2008) Identification of a vesicular nucleotide transporter. Proc Natl Acad Sci USA 105:5683–5686

    Article  PubMed  CAS  Google Scholar 

  47. Sreedharan S, Shaik JH, Olszewski PK, Levine AS, Schioth HB, Fredriksson R (2010) Glutamate, aspartate and nucleotide transporters in the SLC17 family form four main phylogenetic clusters: evolution and tissue expression. BMC Genomics 11:17

    Article  PubMed  CAS  Google Scholar 

  48. Crippa D, Schenk U, Francolini M, Rosa P, Verderio C, Zonta M, Pozzan T, Matteoli M, Carmignoto G (2006) Synaptobrevin2-expressing vesicles in rat astrocytes: insights into molecular characterization, dynamics and exocytosis. J Physiol 570:567–582

    Article  PubMed  CAS  Google Scholar 

  49. Zhang Q, Fukuda M, Van Bockstaele E, Pascual O, Haydon PG (2004) Synaptotagmin IV regulates glial glutamate release. Proc Natl Acad Sci USA 101:9441–9446

    Article  PubMed  CAS  Google Scholar 

  50. Dai H, Shin OH, Machius M, Tomchick DR, Sudhof TC, Rizo J (2004) Structural basis for the evolutionary inactivation of Ca2+ binding to synaptotagmin 4. Nat Struct Mol Biol 11:844–849

    Article  PubMed  CAS  Google Scholar 

  51. Bezzi P, Gundersen V, Galbete JL, Seifert G, Steinhauser C, Pilati E, Volterra A (2004) Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat Neurosci 7:613–620

    Article  PubMed  CAS  Google Scholar 

  52. Malarkey EB, Parpura V (2011) Temporal characteristics of vesicular fusion in astrocytes: examination of synaptobrevin 2-laden vesicles at single vesicle resolution. J Physiol 589:4271–4300

    PubMed  CAS  Google Scholar 

  53. Calegari F, Coco S, Taverna E, Bassetti M, Verderio C, Corradi N, Matteoli M, Rosa P (1999) A regulated secretory pathway in cultured hippocampal astrocytes. J Biol Chem 274:22539–22547

    Article  PubMed  CAS  Google Scholar 

  54. Coco S, Calegari F, Pravettoni E, Pozzi D, Taverna E, Rosa P, Matteoli M, Verderio C (2003) Storage and release of ATP from astrocytes in culture. J Biol Chem 278:1354–1362

    Article  PubMed  CAS  Google Scholar 

  55. Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG (1994) Glutamate-mediated astrocyte-neuron signalling. Nature 369:744–747

    Article  PubMed  CAS  Google Scholar 

  56. Araque A, Parpura V, Sanzgiri RP, Haydon PG (1998) Glutamate-dependent astrocyte modulation of synaptic transmission between cultured hippocampal neurons. Eur J Neurosci 10:2129–2142

    Article  PubMed  CAS  Google Scholar 

  57. Araque A, Sanzgiri RP, Parpura V, Haydon PG (1998) Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons. J Neurosci 18:6822–6829

    PubMed  CAS  Google Scholar 

  58. Fellin T, Pascual O, Gobbo S, Pozzan T, Haydon PG, Carmignoto G (2004) Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43:729–743

    Article  PubMed  CAS  Google Scholar 

  59. Hassinger TD, Atkinson PB, Strecker GJ, Whalen LR, Dudek FE, Kossel AH, Kater SB (1995) Evidence for glutamate-mediated activation of hippocampal neurons by glial calcium waves. J Neurobiol 28:159–170

    Article  PubMed  CAS  Google Scholar 

  60. Perea G, Araque A (2007) Astrocytes potentiate transmitter release at single hippocampal synapses. Science 317:1083–1086

    Article  PubMed  CAS  Google Scholar 

  61. Santello M, Volterra A (2009) Synaptic modulation by astrocytes via Ca2+-dependent glutamate release. Neuroscience 158:253–259

    Article  PubMed  CAS  Google Scholar 

  62. Mothet JP, Parent AT, Wolosker H, Brady RO Jr, Linden DJ, Ferris CD, Rogawski MA, Snyder SH (2000) d-serine is an endogenous ligand for the glycine site of the N-methyl-d-aspartate receptor. Proc Natl Acad Sci USA 97:4926–4931

    Article  PubMed  CAS  Google Scholar 

  63. Stevens ER, Esguerra M, Kim PM, Newman EA, Snyder SH, Zahs KR, Miller RF (2003) d-serine and serine racemase are present in the vertebrate retina and contribute to the physiological activation of NMDA receptors. Proc Natl Acad Sci USA 100:6789–6794

    Article  PubMed  CAS  Google Scholar 

  64. Henneberger C, Papouin T, Oliet SH, Rusakov DA (2010) Long-term potentiation depends on release of d-serine from astrocytes. Nature 463:232–236

    Article  PubMed  CAS  Google Scholar 

  65. Yang Y, Ge W, Chen Y, Zhang Z, Shen W, Wu C, Poo M, Duan S (2003) Contribution of astrocytes to hippocampal long-term potentiation through release of d-serine. Proc Natl Acad Sci USA 100:15194–15199

    Article  PubMed  CAS  Google Scholar 

  66. Verkhratsky A, Krishtal OA, Burnstock G (2009) Purinoceptors on neuroglia. Mol Neurobiol 39:190–208

    Article  PubMed  CAS  Google Scholar 

  67. Burnstock G, Fredholm BB, Verkhratsky A (2011) Adenosine and ATP receptors in the brain. Curr Top Med Chem 11:973–1011

    Article  PubMed  CAS  Google Scholar 

  68. Arcuino G, Lin JH, Takano T, Liu C, Jiang L, Gao Q, Kang J, Nedergaard M (2002) Intercellular calcium signaling mediated by point-source burst release of ATP. Proc Natl Acad Sci USA 99:9840–9845

    Article  PubMed  CAS  Google Scholar 

  69. Cotrina ML, Lin JH, Lopez-Garcia JC, Naus CC, Nedergaard M (2000) ATP-mediated glia signaling. J Neurosci 20:2835–2844

    PubMed  CAS  Google Scholar 

  70. Guthrie PB, Knappenberger J, Segal M, Bennett MV, Charles AC, Kater SB (1999) ATP released from astrocytes mediates glial calcium waves. J Neurosci 19:520–528

    PubMed  CAS  Google Scholar 

  71. Stout CE, Costantin JL, Naus CC, Charles AC (2002) Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J Biol Chem 277:10482–10488

    Article  PubMed  CAS  Google Scholar 

  72. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553

    Article  PubMed  CAS  Google Scholar 

  73. Verderio C, Matteoli M (2001) ATP mediates calcium signaling between astrocytes and microglial cells: modulation by IFN-γ. J Immunol 166:6383–6391

    PubMed  CAS  Google Scholar 

  74. Braet K, Paemeleire K, D’Herde K, Sanderson MJ, Leybaert L (2001) Astrocyte-endothelial cell calcium signals conveyed by two signalling pathways. Eur J Neurosci 13:79–91

    Article  PubMed  CAS  Google Scholar 

  75. Marpegan L, Swanstrom AE, Chung K, Simon T, Haydon PG, Khan SK, Liu AC, Herzog ED, Beaule C (2011) Circadian regulation of ATP release in astrocytes. J Neurosci 31:8342–8350

    Article  PubMed  CAS  Google Scholar 

  76. Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, Sul JY, Takano H, Moss SJ, McCarthy K, Haydon PG (2005) Astrocytic purinergic signaling coordinates synaptic networks. Science 310:113–116

    Article  PubMed  CAS  Google Scholar 

  77. Pangrsic T, Potokar M, Stenovec M, Kreft M, Fabbretti E, Nistri A, Pryazhnikov E, Khiroug L, Giniatullin R, Zorec R (2007) Exocytotic release of ATP from cultured astrocytes. J Biol Chem 282:28749–28758

    Article  PubMed  CAS  Google Scholar 

  78. Zhang Z, Chen G, Zhou W, Song A, Xu T, Luo Q, Wang W, Gu XS, Duan S (2007) Regulated ATP release from astrocytes through lysosome exocytosis. Nat Cell Biol 9:945–953

    Article  PubMed  CAS  Google Scholar 

  79. Jaiswal JK, Fix M, Takano T, Nedergaard M, Simon SM (2007) Resolving vesicle fusion from lysis to monitor calcium-triggered lysosomal exocytosis in astrocytes. Proc Natl Acad Sci USA 104:14151–14156

    Article  PubMed  CAS  Google Scholar 

  80. Li D, Ropert N, Koulakoff A, Giaume C, Oheim M (2008) Lysosomes are the major vesicular compartment undergoing Ca2+-regulated exocytosis from cortical astrocytes. J Neurosci 28:7648–7658

    Article  PubMed  CAS  Google Scholar 

  81. Bezzi P, Carmignoto G, Pasti L, Vesce S, Rossi D, Rizzini BL, Pozzan T, Volterra A (1998) Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391:281–285

    Article  PubMed  CAS  Google Scholar 

  82. Hua X, Malarkey EB, Sunjara V, Rosenwald SE, Li WH, Parpura V (2004) Ca2+-dependent glutamate release involves two classes of endoplasmic reticulum Ca2+ stores in astrocytes. J Neurosci Res 76:86–97

    Article  PubMed  CAS  Google Scholar 

  83. Innocenti B, Parpura V, Haydon PG (2000) Imaging extracellular waves of glutamate during calcium signaling in cultured astrocytes. J Neurosci 20:1800–1808

    PubMed  CAS  Google Scholar 

  84. Montana V, Ni Y, Sunjara V, Hua X, Parpura V (2004) Vesicular glutamate transporter-dependent glutamate release from astrocytes. J Neurosci 24:2633–2642

    Article  PubMed  CAS  Google Scholar 

  85. Parpura V, Grubisic V, Verkhratsky A (2011) Ca2+ sources for the exocytotic release of glutamate from astrocytes. Biochim Biophys Acta 1813:984–991

    Article  PubMed  CAS  Google Scholar 

  86. Verkhratsky A, Rodriguez JJ, Parpura V (2012) Calcium signalling in astroglia. Mol Cell Endocrinol 353:45–56

    Article  PubMed  CAS  Google Scholar 

  87. Stout RF Jr, Parpura V (2011) Voltage-gated calcium channel types in cultured C. elegans CEPsh glial cells. Cell Calcium 50:98–108

    Article  PubMed  CAS  Google Scholar 

  88. Malarkey EB, Ni Y, Parpura V (2008) Ca2+ entry through TRPC1 channels contributes to intracellular Ca2+ dynamics and consequent glutamate release from rat astrocytes. Glia 56:821–835

    Article  PubMed  Google Scholar 

  89. Parri HR, Gould TM, Crunelli V (2001) Spontaneous astrocytic Ca2+ oscillations in situ drive NMDAR-mediated neuronal excitation. Nat Neurosci 4:803–812

    Article  PubMed  CAS  Google Scholar 

  90. Yaguchi T, Nishizaki T (2010) Extracellular high K+ stimulates vesicular glutamate release from astrocytes by activating voltage-dependent calcium channels. J Cell Physiol 225:512–518

    Article  PubMed  CAS  Google Scholar 

  91. Paluzzi S, Alloisio S, Zappettini S, Milanese M, Raiteri L, Nobile M, Bonanno G (2007) Adult astroglia is competent for Na+/Ca2+ exchanger-operated exocytotic glutamate release triggered by mild depolarization. J Neurochem 103:1196–1207

    Article  PubMed  CAS  Google Scholar 

  92. Reyes RC, Verkhratsky A, Parpura V (2012) Plasmalemmal Na+/Ca2+ exchanger modulates Ca2+-dependent exocytotic release of glutamate from rat cortical astrocytes. ASN Neuro (E-pub ahead of print). doi:10.1042/AN20110059

  93. Reyes RC, Parpura V (2008) Mitochondria modulate Ca2+-dependent glutamate release from rat cortical astrocytes. J Neurosci 28:9682–9691

    Article  PubMed  CAS  Google Scholar 

  94. Reyes RC, Perry G, Lesort M, Parpura V (2011) Immunophilin deficiency augments Ca2+-dependent glutamate release from mouse cortical astrocytes. Cell Calcium 49:23–34

    Article  PubMed  CAS  Google Scholar 

  95. Lee M, McGeer EG, McGeer PL (2011) Mechanisms of GABA release from human astrocytes. Glia 59:1600–1611

    Article  PubMed  Google Scholar 

  96. Dvorzhak A, Myakhar O, Unichenko P, Kirmse K, Kirischuk S (2010) Estimation of ambient GABA levels in layer I of the mouse neonatal cortex in brain slices. J Physiol 588:2351–2360

    Article  PubMed  CAS  Google Scholar 

  97. Santhakumar V, Hanchar HJ, Wallner M, Olsen RW, Otis TS (2006) Contributions of the GABAA receptor α6 subunit to phasic and tonic inhibition revealed by a naturally occurring polymorphism in the α6 gene. J Neurosci 26:3357–3364

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  99. Herman MA, Jahr CE (2007) Extracellular glutamate concentration in hippocampal slice. J Neurosci 27:9736–9741

    Article  PubMed  CAS  Google Scholar 

  100. Liu HT, Tashmukhamedov BA, Inoue H, Okada Y, Sabirov RZ (2006) Roles of two types of anion channels in glutamate release from mouse astrocytes under ischemic or osmotic stress. Glia 54:343–357

    Article  PubMed  Google Scholar 

  101. Nilius B, Eggermont J, Voets T, Buyse G, Manolopoulos V, Droogmans G (1997) Properties of volume-regulated anion channels in mammalian cells. Prog Biophys Mol Biol 68:69–119

    Article  PubMed  CAS  Google Scholar 

  102. Fields RD (2011) Nonsynaptic and nonvesicular ATP release from neurons and relevance to neuron-glia signaling. Semin Cell Dev Biol 22:214–219

    Article  PubMed  CAS  Google Scholar 

  103. Lee S, Yoon BE, Berglund K, Oh SJ, Park H, Shin HS, Augustine GJ, Lee CJ (2010) Channel-mediated tonic GABA release from glia. Science 330:790–796

    Article  PubMed  CAS  Google Scholar 

  104. Baroja-Mazo A, Barbera-Cremades M, Pelegrin P (2012) The participation of plasma membrane hemichannels to purinergic signaling. Biochim Biophys Acta (in press)

  105. Bao L, Locovei S, Dahl G (2004) Pannexin membrane channels are mechanosensitive conduits for ATP. FEBS Lett 572:65–68

    Article  PubMed  CAS  Google Scholar 

  106. Ma W, Compan V, Zheng W, Martin E, North RA, Verkhratsky A, Surprenant A (2012) Pannexin 1 forms an anion-selective channel. Pflügers Arch 463:585–592

    Article  PubMed  CAS  Google Scholar 

  107. Hofer A, Dermietzel R (1998) Visualization and functional blocking of gap junction hemichannels (connexons) with antibodies against external loop domains in astrocytes. Glia 24:141–154

    Article  PubMed  CAS  Google Scholar 

  108. Kang J, Kang N, Lovatt D, Torres A, Zhao Z, Lin J, Nedergaard M (2008) Connexin 43 hemichannels are permeable to ATP. J Neurosci 28:4702–4711

    Article  PubMed  CAS  Google Scholar 

  109. Ye ZC, Wyeth MS, Baltan-Tekkok S, Ransom BR (2003) Functional hemichannels in astrocytes: a novel mechanism of glutamate release. J Neurosci 23:3588–3596

    PubMed  CAS  Google Scholar 

  110. North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82:1013–1067

    PubMed  CAS  Google Scholar 

  111. Pelegrin P, Surprenant A (2009) The P2X7 receptor-pannexin connection to dye uptake and IL-1β release. Purinergic Signal 5:129–137

    Article  PubMed  CAS  Google Scholar 

  112. Pellegatti P, Falzoni S, Pinton P, Rizzuto R, Di Virgilio F (2005) A novel recombinant plasma membrane-targeted luciferase reveals a new pathway for ATP secretion. Mol Biol Cell 16:3659–3665

    Article  PubMed  CAS  Google Scholar 

  113. Suadicani SO, Brosnan CF, Scemes E (2006) P2X7 receptors mediate ATP release and amplification of astrocytic intercellular Ca2+ signaling. J Neurosci 26:1378–1385

    Article  PubMed  CAS  Google Scholar 

  114. Duan S, Anderson CM, Keung EC, Chen Y, Swanson RA (2003) P2X7 receptor-mediated release of excitatory amino acids from astrocytes. J Neurosci 23:1320–1328

    PubMed  CAS  Google Scholar 

  115. Kinney GA (2005) GAT-3 transporters regulate inhibition in the neocortex. J Neurophysiol 94:4533–4537

    Article  PubMed  CAS  Google Scholar 

  116. Kirmse K, Kirischuk S (2006) Ambient GABA constrains the strength of GABAergic synapses at Cajal-Retzius cells in the developing visual cortex. J Neurosci 26:4216–4227

    Article  PubMed  CAS  Google Scholar 

  117. Kirischuk S, Kettenmann H, Verkhratsky A (2007) Membrane currents and cytoplasmic sodium transients generated by glutamate transport in Bergmann glial cells. Pflugers Arch 454:245–252

    Article  PubMed  CAS  Google Scholar 

  118. Pow DV (2001) Visualising the activity of the cystine-glutamate antiporter in glial cells using antibodies to aminoadipic acid, a selectively transported substrate. Glia 34:27–38

    Article  PubMed  CAS  Google Scholar 

  119. Warr O, Takahashi M, Attwell D (1999) Modulation of extracellular glutamate concentration in rat brain slices by cystine-glutamate exchange. J Physiol 514(Pt 3):783–793

    Article  PubMed  CAS  Google Scholar 

  120. Deitmer JW, Verkhratsky AJ, Lohr C (1998) Calcium signalling in glial cells. Cell Calcium 24:405–416

    Article  PubMed  CAS  Google Scholar 

  121. Verkhratsky A, Kettenmann H (1996) Calcium signalling in glial cells. Trends Neurosci 19:346–352

    Article  PubMed  CAS  Google Scholar 

  122. Verkhratsky A, Orkand RK, Kettenmann H (1998) Glial calcium: homeostasis and signaling function. Physiol Rev 78:99–141

    PubMed  CAS  Google Scholar 

  123. Verkhratsky A, Steinhauser C (2000) Ion channels in glial cells. Brain Res Brain Res Rev 32:380–412

    Article  PubMed  CAS  Google Scholar 

  124. Verkhratsky A (2010) Physiology of neuronal-glial networking. Neurochem Int 57:332–343

    Article  PubMed  CAS  Google Scholar 

  125. Kirischuk S, Matiash V, Kulik A, Voitenko N, Kostyuk P, Verkhratsky A (1996) Activation of P2-purino-, α1-adreno and H1-histamine receptors triggers cytoplasmic calcium signalling in cerebellar Purkinje neurons. Neuroscience 73:643–647

    Article  PubMed  CAS  Google Scholar 

  126. Kirischuk S, Moller T, Voitenko N, Kettenmann H, Verkhratsky A (1995) ATP-induced cytoplasmic calcium mobilization in Bergmann glial cells. J Neurosci 15:7861–7871

    PubMed  CAS  Google Scholar 

  127. Kirischuk S, Tuschick S, Verkhratsky A, Kettenmann H (1996) Calcium signalling in mouse Bergmann glial cells mediated by α1-adrenoreceptors and H1 histamine receptors. Eur J Neurosci 8:1198–1208

    Article  PubMed  CAS  Google Scholar 

  128. Kirchhoff F, Mulhardt C, Pastor A, Becker CM, Kettenmann H (1996) Expression of glycine receptor subunits in glial cells of the rat spinal cord. J Neurochem 66:1383–1390

    Article  PubMed  CAS  Google Scholar 

  129. Miyazaki I, Asanuma M, Diaz-Corrales FJ, Miyoshi K, Ogawa N (2004) Direct evidence for expression of dopamine receptors in astrocytes from basal ganglia. Brain Res 1029:120–123

    Article  PubMed  CAS  Google Scholar 

  130. Jabs R, Kirchhoff F, Kettenmann H, Steinhauser C (1994) Kainate activates Ca2+-permeable glutamate receptors and blocks voltage-gated K + currents in glial cells of mouse hippocampal slices. Pflugers Arch 426:310–319

    Article  PubMed  CAS  Google Scholar 

  131. Muller T, Moller T, Berger T, Schnitzer J, Kettenmann H (1992) Calcium entry through kainate receptors and resulting potassium-channel blockade in Bergmann glial cells. Science 256:1563–1566

    Article  PubMed  CAS  Google Scholar 

  132. Lalo U, Pankratov Y, Kirchhoff F, North RA, Verkhratsky A (2006) NMDA receptors mediate neuron-to-glia signaling in mouse cortical astrocytes. J Neurosci 26:2673–2683

    Article  PubMed  CAS  Google Scholar 

  133. Lalo U, Pankratov Y, Parpura V, Verkhratsky A (2011) Ionotropic receptors in neuronal-astroglial signalling: what is the role of “excitable” molecules in non-excitable cells. Biochim Biophys Acta 1813:992–1002

    Article  PubMed  CAS  Google Scholar 

  134. Ziak D, Chvatal A, Sykova E (1998) Glutamate-, kainate- and NMDA-evoked membrane currents in identified glial cells in rat spinal cord slice. Physiol Res 47:365–375

    PubMed  CAS  Google Scholar 

  135. Palygin O, Lalo U, Pankratov Y (2011) Distinct pharmacological and functional properties of NMDA receptors in mouse cortical astrocytes. Br J Pharmacol

  136. Palygin O, Lalo U, Verkhratsky A, Pankratov Y (2010) Ionotropic NMDA and P2X1/5 receptors mediate synaptically induced Ca2+ signalling in cortical astrocytes. Cell Calcium 48:225–231

    Article  PubMed  CAS  Google Scholar 

  137. Verkhratsky A, Kirchhoff F (2007) NMDA Receptors in Glia. Neuroscientist 13:28–37

    CAS  Google Scholar 

  138. Kirischuk S, Kirchhoff F, Matyash V, Kettenmann H, Verkhratsky A (1999) Glutamate-triggered calcium signalling in mouse Bergmann glial cells in situ: role of inositol-1,4,5-trisphosphate-mediated intracellular calcium release. Neuroscience 92:1051–1059

    Article  PubMed  CAS  Google Scholar 

  139. Aronica E, van Vliet EA, Mayboroda OA, Troost D, da Silva FH, Gorter JA (2000) Upregulation of metabotropic glutamate receptor subtype mGluR3 and mGluR5 in reactive astrocytes in a rat model of mesial temporal lobe epilepsy. Eur J Neurosci 12:2333–2344

    Article  PubMed  CAS  Google Scholar 

  140. Petralia RS, Wang YX, Niedzielski AS, Wenthold RJ (1996) The metabotropic glutamate receptors, mGluR2 and mGluR3, show unique postsynaptic, presynaptic and glial localizations. Neuroscience 71:949–976

    Article  PubMed  CAS  Google Scholar 

  141. Tamaru Y, Nomura S, Mizuno N, Shigemoto R (2001) Distribution of metabotropic glutamate receptor mGluR3 in the mouse CNS: differential location relative to pre- and postsynaptic sites. Neuroscience 106:481–503

    Article  PubMed  CAS  Google Scholar 

  142. Abbracchio MP, Burnstock G, Verkhratsky A, Zimmermann H (2009) Purinergic signalling in the nervous system: an overview. Trends Neurosci 32:19–29

    Article  PubMed  CAS  Google Scholar 

  143. Boison D, Chen JF, Fredholm BB (2010) Adenosine signaling and function in glial cells. Cell Death Differ 17:1071–1082

    Article  PubMed  CAS  Google Scholar 

  144. Lalo U, Pankratov Y, Wichert SP, Rossner MJ, North RA, Kirchhoff F, Verkhratsky A (2008) P2X1 and P2X5 subunits form the functional P2X receptor in mouse cortical astrocytes. J Neurosci 28:5473–5480

    Article  PubMed  CAS  Google Scholar 

  145. Lalo U, Verkhratsky A, Pankratov Y (2011) Ionotropic ATP receptors in neuronal-glial communication. Semin Cell Dev Biol 22:220–228

    Article  PubMed  CAS  Google Scholar 

  146. Pannicke T, Fischer W, Biedermann B, Schadlich H, Grosche J, Faude F, Wiedemann P, Allgaier C, Illes P, Burnstock G, Reichenbach A (2000) P2X7 receptors in Muller glial cells from the human retina. J Neurosci 20:5965–5972

    PubMed  CAS  Google Scholar 

  147. Ballerini P, Rathbone MP, Di Iorio P, Renzetti A, Giuliani P, D’Alimonte I, Trubiani O, Caciagli F, Ciccarelli R (1996) Rat astroglial P2Z (P2X7) receptors regulate intracellular calcium and purine release. NeuroReport 7:2533–2537

    Article  PubMed  CAS  Google Scholar 

  148. Fumagalli M, Brambilla R, D’Ambrosi N, Volonte C, Matteoli M, Verderio C, Abbracchio MP (2003) Nucleotide-mediated calcium signaling in rat cortical astrocytes: Role of P2X and P2Y receptors. Glia 43:203–218

    Article  Google Scholar 

  149. Nobile M, Monaldi I, Alloisio S, Cugnoli C, Ferroni S (2003) ATP-induced, sustained calcium signalling in cultured rat cortical astrocytes: evidence for a non-capacitative, P2X7-like-mediated calcium entry. FEBS Lett 538:71–76

    Article  PubMed  CAS  Google Scholar 

  150. Hamilton N, Vayro S, Kirchhoff F, Verkhratsky A, Robbins J, Gorecki DC, Butt AM (2008) Mechanisms of ATP- and glutamate-mediated calcium signaling in white matter astrocytes. Glia 56:734–749

    Article  PubMed  Google Scholar 

  151. Norenberg W, Schunk J, Fischer W, Sobottka H, Riedel T, Oliveira JF, Franke H, Illes P (2010) Electrophysiological classification of P2X7 receptors in rat cultured neocortical astroglia. Br J Pharmacol 160:1941–1952

    Article  PubMed  CAS  Google Scholar 

  152. Oliveira JF, Riedel T, Leichsenring A, Heine C, Franke H, Krugel U, Norenberg W, Illes P (2011) Rodent cortical astroglia express in situ functional P2X7 receptors sensing pathologically high ATP concentrations. Cereb Cortex 21:806–820

    Article  PubMed  Google Scholar 

  153. Illes P, Verkhratsky A, Burnstock G, Franke H (2011) P2X receptors and their roles in astroglia in the central and peripheral nervous system. Neuroscientist. doi:10.1177/1073858411418524

  154. Franke H, Grosche J, Schadlich H, Krugel U, Allgaier C, Illes P (2001) P2X receptor expression on astrocytes in the nucleus accumbens of rats. Neuroscience 108:421–429

    Article  PubMed  CAS  Google Scholar 

  155. Ashour F, Deuchars J (2004) Electron microscopic localisation of P2X4 receptor subunit immunoreactivity to pre- and post-synaptic neuronal elements and glial processes in the dorsal vagal complex of the rat. Brain Res 1026:44–55

    Article  PubMed  CAS  Google Scholar 

  156. Kanjhan R, Housley GD, Thorne PR, Christie DL, Palmer DJ, Luo L, Ryan AF (1996) Localization of ATP-gated ion channels in cerebellum using P2x2R subunit-specific antisera. NeuroReport 7:2665–2669

    Article  PubMed  CAS  Google Scholar 

  157. Loesch A, Burnstock G (1998) Electron-immunocytochemical localization of P2X1 receptors in the rat cerebellum. Cell Tissue Res 294:253–260

    Article  PubMed  CAS  Google Scholar 

  158. Kukley M, Barden JA, Steinhauser C, Jabs R (2001) Distribution of P2X receptors on astrocytes in juvenile rat hippocampus. Glia 36:11–21

    Article  PubMed  CAS  Google Scholar 

  159. Jabs R, Matthias K, Grote A, Grauer M, Seifert G, Steinhauser C (2007) Lack of P2X receptor mediated currents in astrocytes and GluR type glial cells of the hippocampal CA1 region. Glia 55:1648–1655

    Article  PubMed  Google Scholar 

  160. Abbracchio MP, Ceruti S (2006) Roles of P2 receptors in glial cells: focus on astrocytes. Purinergic Signal 2:595–604

    Article  PubMed  CAS  Google Scholar 

  161. Verkhratsky A, (2009) Neurotransmitter receptors in astrocytes In: Parpura V, Haydon PG (eds) Astrocytes in (patho)physiology of the nervous system. Springer, New York, pp 49–67

  162. Nedergaard M, Verkhratsky A (2012) Artifact versus reality-How astrocytes contribute to synaptic events? Glia (E-pub ahead of print). doi: 10.1002/glia.22288

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Acknowledgments

Authors research was supported by Alzheimer’s Research Trust (UK) Programme Grant (ART/PG2004A/1) to AV and JJR; by National Science Foundation (CBET 0943343) grant to VP, by the Grant Agency of the Czech Republic (GACR 309/09/1696) to JJR and (GACR 305/08/1384) to AV. The Spanish Government, Plan Nacional de I+D+I 2008–2011 and ISCIII- Subdirección General de Evaluación y Fomento de la Investigación (PI10/02738) to JJR and AV and the Government of the Basque Country grant (AE-2010-1-28, AEGV10/16) to JJR.

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Authors and Affiliations

  1. Faculty of Life Sciences, The University of Manchester, Manchester, M13 9PT, UK

    Alexei Verkhratsky

  2. IKERBASQUE, Basque Foundation for Science, 48011, Bilbao, Spain

    Alexei Verkhratsky, José Julio Rodríguez & Vladimir Parpura

  3. Department of Neurosciences, University of the Basque Country UPV/EHU, 48940, Leioa, Spain

    Alexei Verkhratsky & José Julio Rodríguez

  4. Institute of Experimental Medicine, ASCR, Videnska 1083, 142 20, Prague, Czech Republic

    Alexei Verkhratsky & José Julio Rodríguez

  5. Department of Neurobiology, Center for Glial Biology in Medicine, Atomic Force Microscopy and Nanotechnology Laboratories, Civitan International Research Center, Evelyn F. McKnight Brain Institute, University of Alabama, 1719 6th Avenue South, CIRC 429, Birmingham, AL, 35294, USA

    Vladimir Parpura

  6. School of Medicine, University of Split, 21000, Split, Croatia

    Vladimir Parpura

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  1. Alexei Verkhratsky
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  2. José Julio Rodríguez
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Correspondence to Alexei Verkhratsky or Vladimir Parpura.

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Special Issue: In Honor of Leif Hertz.

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Verkhratsky, A., Rodríguez, J.J. & Parpura, V. Neurotransmitters and Integration in Neuronal-Astroglial Networks. Neurochem Res 37, 2326–2338 (2012). https://doi.org/10.1007/s11064-012-0765-6

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  • DOI: https://doi.org/10.1007/s11064-012-0765-6

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