Abstract
Adenosine triphosphate (ATP) acts as a fast excitatory transmitter in several regions of the central nervous system (CNS) including the medial habenula, dorsal horn, locus coeruleus, hippocampus, and somatosensory cortex. Postsynaptic actions of ATP are mediated through an extended family of P2X receptors, widely expressed throughout the CNS. ATP is released via several pathways, including exocytosis from presynaptic terminals and diffusion through large transmembrane pores (e.g., hemichannels, P2X7 receptors, or volume-sensitive chloride channels) expressed in astroglial membranes. In presynaptic terminals, ATP is accumulated and stored in the synaptic vesicles. In different presynaptic terminals, these vesicles may contain ATP only or ATP and another neurotransmitter [e.g., γ-amino-butyric acid (GABA) or glutamate]; in the latter case, two transmitters can be coreleased. Here, we discuss the mechanisms of vesicular release of ATP in the CNS and present our own data, which indicate that in central neuronal terminals, ATP is primarily stored and released from distinct pool of vesicles; the release of ATP is not synchronized either with GABA or with glutamate.
Similar content being viewed by others
References
Ahmad S, Ahmad A, McConville G, Schneider BK, Allen CB, Manzer R, Mason RJ, White CW (2005) Lung epithelial cells release ATP during ozone exposure: signaling for cell survival. Free Radic Biol Med 39:213–226
Aleu J, Martin-Satue M, Navarro P, Perez de Lara I, Bahima L, Marsal J, Solsona C (2003) Release of ATP induced by hypertonic solutions in Xenopus oocytes. J Physiol (London) 547:209–219
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
Aspinwall CA, Yeung ES (2005) Screening populations of individual cells for secretory heterogeneity. Anal Bioanal Chem 381:660–666
Bankston LA, Guidotti G (1996) Characterization of ATP transport into chromaffin granule ghosts—synergy of ATP and serotonin accumulation in chromaffin granule ghosts. J Biol Chem 271:17132–17138
Bardoni R, Goldstein PA, Lee CJ, Gu JG, MacDermott AB (1997) ATP P2X receptors mediate fast synaptic transmission in the dorsal horn of the rat spinal cord. J Neurosci 17:5297–5304
Bergendorff A, Uvnas B (1973) Storage properties of rat mast cell granules in vitro. Acta Physiol Scand 87:213–222
Bodin P, Burnstock G (2001) Purinergic signalling: ATP release. Neurochem Res 26:959–969
Cunha RA, Vizi ES, Ribeiro JA, Sebastiao AM (1996) Preferential release of ATP and its extracellular catabolism as a source of adenosine upon high—but not low—frequency stimulation of rat hippocampal slices. J Neurochem 67:2180–2187
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
Darby M, Kuzmiski JB, Panenka W, Feighan D, MacVicar BA (2003) ATP released from astrocytes during swelling activates chloride channels. J Neurophysiol 89:1870–1877
Edwards FA, Gibb AJ, Colquhoun D (1992) ATP receptor-mediated synaptic currents in the central nervous system. Nature 359:144–147
Edwards FA, Robertson SJ, Gibb AJ (1997) Properties of ATP receptor-mediated synaptic transmission in the rat medial habenula. Neuropharmacology 36:1253–1268
Fabbro A, Skorinkin A, Grandolfo M, Nistri A, Giniatullin R (2004) Quantal release of ATP from clusters of PC12 cells. J Physiol 560:505–517
Farinas I, Solsona C, Marsal J (1992) Omega-conotoxin differentially blocks acetylcholine and adenosine triphosphate releases from Torpedo synaptosomes. Neuroscience 47:641–648
Gualix J, Pintor J, Miras-Portugal MT (1999) Characterization of nucleotide transport into rat brain synaptic vesicles. J Neurochem 73:1098–1104
Jo YH, Role LW (2002) Coordinate release of ATP and GABA at in vitro synapses of lateral hypothalamic neurons. J Neurosci 22:4794–4804
Jo YH, Schlichter R (1999) Synaptic corelease of ATP and GABA in cultured spinal neurons. Nat Neurosci 2:241–245
Katz B (1979) Elementary components of synaptic transmission. Naturwissenschaften 66:606–610
Kelly R (1993) Storage and release of neurotransmitters. Cell 72:43–54 (Suppl)
Khakh BS (2001) Molecular physiology of P2X receptors and ATP signalling at synapses. Nat Rev Neurosci 2:165–174
Lalo UV, Voitenko NV, Kostyuk PG (1998) Iono- and metabotropically induced purinergic calcium signalling in rat neocortical neurons. Brain Res 799:285–291
Lange K, Brandt U (1993) Rapid uptake of calcium, ATP, and inositol 1,4,5-trisphosphate via cation and anion channels into surface-derived vesicles from HIT cells containing the inositol 1,4,5-trisphosphate-sensitive calcium store. FEBS Lett 325:205–209
Lazarowski ER, Boucher RC, Harden TK (2003) Mechanisms of release of nucleotides and integration of their action as P2X- and P2Y-receptor activating molecules. Mol Pharmacol 64:785–795
Lee DA, Witzemann V (1983) Photoaffinity labeling of a synaptic vesicle specific nucleotide transport system from Torpedo marmorata. Biochemistry 22:6123–6130
Luqmani YA (1981) Nucleotide uptake by isolated cholinergic synaptic vesicles: evidence for a carrier of adenosine 5′-triphosphate. Neuroscience 6:1011–1021
Marsal J, Egea G, Solsona C, Rabasseda X, Blasi J (1989) Botulinum toxin type A blocks the morphological changes induced by chemical stimulation on the presynaptic membrane of Torpedo synaptosomes. Proc Natl Acad Sci USA 86:372–376
Morel N, Meunier FM (1981) Simultaneous release of acetylcholine and ATP from stimulated cholinergic synaptosomes. J Neurochem 36:1766–1773
Mori M, Heuss C, Gahwiler BH, Gerber U (2001) Fast synaptic transmission mediated by P2X receptors in CA3 pyramidal cells of rat hippocampal slice cultures. J Physiol 535:115–123
Nieber K, Poelchen W, Illes P (1997) Role of ATP in fast excitatory synaptic potentials in locus coeruleus neurones of the rat. Br J Pharmacol 122:423–430
Norenberg W, Illes P (2000) Neuronal P2X receptors: localisation and functional properties. Naunyn Schmiedebergs Arch Pharmacol 362:324–339
Pankratov YV, Krishtal OA (2003) Distinct quantal features of AMPA and NMDA synaptic currents in hippocampal neurons: implication of glutamate spillover and receptor saturation. Biophys J 85:3375–3387
Pankratov Y, Castro E, Miras-Portugal MT, Krishtal O (1998) A purinergic component of the excitatory postsynaptic current mediated by P2X receptors in the CA1 neurons of the rat hippocampus. Eur J Neurosci 10:3898–3902
Pankratov YV, Lalo UV, Castro E, Miras-Portugal MT, Krishtal OA (1999) ATP receptor-mediated component of the excitatory synaptic transmission in the hippocampus. Prog Brain Res 120:237–249
Pankratov Y, Lalo U, Krishtal O, Verkhratsky A (2002) Ionotropic P2X purinoreceptors mediate synaptic transmission in rat pyramidal neurones of layer II/III of somato-sensory cortex. J Physiol (London) 542:529–536
Pankratov Y, Lalo U, Krishtal O, Verkhratsky A (2003) P2X receptor-mediated excitatory synaptic currents in somatosensory cortex. Mol Cell Neurosci 24:842–849
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
Potter PE, White TD (1982) Lack of effect of 6-hydroxydopamine pretreatment on depolarization-induced release of ATP from rat brain synaptosomes. Eur J Pharmacol 80:143–147
Rabasseda X, Solsona C, Marsal J, Egea G, Bizzini B (1987) ATP release from pure cholinergic synaptosomes is not blocked by tetanus toxin. FEBS Lett 213:337–340
Reigada D, Diez-Perez I, Gorostiza P, Verdaguer A, Gomez de Aranda I, Pineda O, Vilarrasa J, Marsal J, Blasi J, Aleu J, Solsona C (2003) Control of neurotransmitter release by an internal gel matrix in synaptic vesicles. Proc Natl Acad Sci USA 100:3485–3490
Robertson SJ, Edwards FA (1998) ATP and glutamate are released from separate neurones in the rat medial habenula nucleus: frequency dependence and adenosine-mediated inhibition of release. J Physiol 508:691–701
Romanello M, Codognotto A, Bicego M, Pines A, Tell G, D’Andrea P (2005) Autocrine/paracrine stimulation of purinergic receptors in osteoblasts: contribution of vesicular ATP release. Biochem Biophys Res Commun 331:1429–1438
Rubio ME, Soto F (2001) Distinct Localization of P2X receptors at excitatory postsynaptic specializations. J Neurosci 21:641–653
Rusakov DA, Kullman DM (1998) Extrasynaptic glutamate diffusion in the hippocampus: ultrastructural constraints, uptake and receptor activation. J Neurosci 18:3158–3170
Salgado AH, Prado MA, Moraes-Santos T, Romano-Silva MA, Gomez MV (1997) Tityustoxin-induced release of ATP from rat brain cortical synaptosomes. Neurosci Lett 229:113–116
Sawynok J, Downie JW, Reid AR, Cahill CM, White TD (1993) ATP release from dorsal spinal cord synaptosomes: characterization and neuronal origin. Brain Res 610:32–38
Sesti C, Broekman MJ, Drosopoulos JH, Islam N, Marcus AJ, Levi R (2002) EctoNucleotidase in cardiac sympathetic nerve endings modulates ATP-mediated feedback of norepinephrine release. J Pharmacol Exp Ther 300:605–611
Sorra KE, Harris KM (1993) Occurrence and three-dimensional structure of multiple synapses between individual radiatum axons and their target pyramidal cells in hippocampal area CA1. J Neurosci 13
Sperlagh B, Vizi ES (2001) Regulation of purine release. In: Abbrachio MP, Williams M (eds) Purinergic and pyrimidinergic signaling, vol 1. Springer, Berlin Heidelberg New York, pp 180–208
Sperlagh B, Magloczky Z, Vizi ES, Freund TF (1998) The triangular septal nucleus as the major source of ATP release in the rat habenula: a combined neurochemical and morphological study. Neuroscience 86:1195–1207
Sperlagh B, Sershen H, Lajtha A, Vizi ES (1998) Co-release of endogenous ATP and [3H]noradrenaline from rat hypothalamic slices: origin and modulation by alpha2-adrenoceptors. Neuroscience 82:511–520
Stadler H, Fenwick EM (1983) Cholinergic synaptic vesicles from Torpedo marmorata contain an atractyloside-binding protein related to the mitochondrial ADP/ATP carrier. Eur J Biochem 136:377–382
Stjarne L (2001) Novel dual ‘small’ vesicle model of ATP- and noradrenaline-mediated sympathetic neuromuscular transmission. Auton Neurosci 87:16–36
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
Stricker C, Field AC, Redman S (1996) Statistical analysis of amplitude fluctuations in EPSCs evoked in rat CA1 pyramidal neurons in vitro. J Physiol (London) 490:419–441
Suadicani SO, Brosnan CF, Scemes E (2006) P2X7 receptors mediate ATP release and amplification of astrocytic intercellular Ca2+ signaling. J Neurosci 26:1378–1385
Sudhof TC (2004) The synaptic vesicle cycle. Annu Rev Neurosci 27:509–547
Terrian DM, Hernandez PG, Rea MA, Peters RI (1989) ATP release, adenosine formation, and modulation of dynorphin and glutamic acid release by adenosine analogues in rat hippocampal mossy fiber synaptosomes. J Neurochem 53:1390–1399
Uvnas B (1974) The molecular basis for the storage and release of histamine in rat mast cell granules. Life Sci 14:2355–2366
Van der Kloot W (2003) Loading and recycling of synaptic vesicles in the Torpedo electric organ and the vertebrate neuromuscular junction. Prog Neurobiol 71:269–303
White TD (1977) Direct detection of depolarisation-induced release of ATP from a synaptosomal preparation. Nature 267:67–68
White TD, MacDonald WF (1990) Neural release of ATP and adenosine. Ann N Y Acad Sci 603:287–298 (discussion 298–299)
White T, Potter P, Wonnacott S (1980) Depolarisation-induced release of ATP from cortical synaptosomes is not associated with acetylcholine release. J Neurochem 34:1109–1112
Wieraszko A, Goldsmith G, Seyfried TN (1989) Stimulation-dependent release of adenosine triphosphate from hippocampal slices. Brain Res 485:244–250
Zhang JM, Wang HK, Ye CQ, Ge W, Chen Y, Jiang ZL, Wu CP, Poo MM, Duan S (2003) ATP released by astrocytes mediates glutamatergic activity-dependent heterosynaptic suppression. Neuron 40:971–982
Zisapel N, Zurgil N (1979) Studies on synaptic vesicles in mammalian brain characterization of highly purified synaptic vesicles from bovine cerebral cortex. Brain Res 178:297–310
Acknowledgement
This research was supported by The Wellcome Trust.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Pankratov, Y., Lalo, U., Verkhratsky, A. et al. Vesicular release of ATP at central synapses. Pflugers Arch - Eur J Physiol 452, 589–597 (2006). https://doi.org/10.1007/s00424-006-0061-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-006-0061-x