Purinergic Signalling (2007) 3:299–310 an undifferentiated line of cells able to originate a number of different cell lineages (adipocytes, chondrocytes, osteoblasts, neurones), spontaneously release ATP into the extracellular space and express functional purinergic P2 receptors, which modulate different kinds of membrane currents, and that ATP, during the early stages of culture, inhibits proliferation indicates an autocrine/paracrine mechanism of action for extracellular ATP in modulating cell functions of undifferen- tiated stem cells at early developmental stages. Such effects may be important in brain neurogenesis during development and in responses to neurodegenerative stimuli. Acknowledgements The present work was supported by Fondazione Monte dei Paschi of Siena, Siena, Italy. References 1. Burnstock G, Dumsday B, Smythe A (1972) Atropine resistant excitation of the urinary bladder: the possibility of transmission via nerves releasing a purine nucleotide. Br J Pharmacol 44:451–461 2. Burnstock G, Cocks T, Kasakov L et al (1978) Direct evidence for ATP release from non-adrenergic, non-cholinergic (“purinergic”) nerves in the guinea-pig taenia coli and bladder. Eur J Pharmacol 49:145–149 3. Fredholm BB, IJzerman AP, Jacobson KA et al (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552 4. Abbracchio MP, Burnstock G (1994) Purinoceptors: are there families of P2X and P2Y purinoceptors? Pharmacol Ther 64:445–475 5. North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82:1013–1067 6. Ciana P, Fumagalli M, Trincavelli ML et al (2006) The orphan receptor GPR17 identified as a new dual uracil nucleotides/ cysteinyl-leukotrienes receptor. EMBO J 25:4615–4627 7. Cunha RA, Sebastiao AM, Ribeiro JA (1998) Inhibition by ATP of hippocampal synaptic transmission requires localized extracellular catabolism by ecto-nucleotidases into adenosine and channeling to adenosine A1 receptors. J Neurosci 18:1987–1995 8. Dunwiddie TV, Diao L, Proctor WR (1997) Adenine nucleotides undergo rapid, quantitative conversion to adenosine in the extracellular space in rat hippocampus. J Neurosci 17:7673–7682 9. O’Kane EM, Stone TW (1998) Interaction between adenosine A1 and A2 receptor-mediated responses in the rat hippocampus in vitro. Eur J Pharmacol 362:17–25 10. Masino SA, Diao L, Illes P et al (2002) Modulation of hippocampal glutamatergic transmission by ATP is dependent on adenosine A1 receptors. J Pharmacol Exp Ther 303:356–363 11. Zimmermann H, Braun N (1996) Extracellular metabolism of nucleotides in the nervous system. J Auton Pharmacol 16:397–400 12. Rodrigues RJ, Almeida T, Richardson PJ et al (2005) Dual presynaptic control by ATP of glutamate release via facilitatory P2X1, P2X2/3, and P2X3 and inhibitory P2Y1, P2Y2, and/or P2Y4 receptors in the rat hippocampus. J Neurosci 25:6286–6295 13. Mendoza-Fernandez V, Andrew RD, Barajas-Lopez C (2000) ATP inhibits glutamate synaptic release by acting at P2Y receptors in pyramidal neurons of hippocampal slices. J Pharmacol Exp Ther 293:172–179 14. Luthardt J, Borvendeg SJ, Sperlagh B et al (2003) P2Y(1) receptor activation inhibits NMDA receptor-channels in layer V pyramidal neurons of the rat prefrontal and parietal cortex. Neurochem Int 42:161–172 307 15. Coppi E, Pugliese AM, Stephan H et al (2007) Role of P2 purinergic receptors in synaptic transmission under normoxic and ischaemic conditions in the CA1 region of rat hippocampal slices. Purinergic Signalling 3:203 16. Zimmermann H, Braun N, Kegel B et al (1998) New insights into molecular structure and function of ectonucleotidases in the nervous system. Neurochem Int 32:421–425 17. Zimmermann H (2000) Extracellular metabolism of ATP and other nucleotides. Naunyn Schmiedebergs Arch Pharmacol 362:299–309 18. Iqbal J, Vollmayer P, Braun N et al (2007) A capillary electrophoresis method for the characterization of ecto-nucleoside triphosphate diphosphohydrolases (NTPDase) and the analysis of inhibitors by in-capillary enzymatic microreaction. Purinergic Signalling 1:349– 358 19. Kukulski F, Komoszynski M (2003) Purification and characteriza- tion of NTPDase1 (ecto-apyrase) and NTPDase2 (ecto-ATPase) from porcine brain cortex synaptosomes. Eur J Biochem 270:3447– 3454 20. Muller CE, Iqbal J, Baqi Y et al (2006) Polyoxometalates-a new class of potent ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) inhibitors. Bioorg Med Chem Lett 16:5943–5947 21. Wieraszko A, Seyfried TN (1989) ATP-induced synaptic potentiation in hippocampal slices. Brain Res 491:356–359 22. Fujii S, Kato H, Furuse H et al (1995) The mechanism of ATP- induced long-term potentiation involves extracellular phosphoryla- tion of membrane proteins in guinea-pig hippocampal CA1 neurons. Neurosci Lett 187:130–132 23. Fujii S, Kato H, Kuroda Y (1999) Extracellular adenosine 5′- triphosphate plus activation of glutamatergic receptors induces long-term potentiation in CA1 neurons of guinea pig hippocam- pal slices. Neurosci Lett 276:21–24 24. Fujii S, Kato H, Kuroda Y (2002) Cooperativity between extracellular adenosine 5′-triphosphate and activation of N-methyl- D-aspartate receptors in long-term potentiation induction in hippo- campal CA1 neurons. Neuroscience 113:617–628 25. O’Kane EM, Stone TW (2000) Characterisation of ATP-induced facilitation of transmission in rat hippocampus. Eur J Pharmacol 409:159–166 26. Abrams TW, Kandel ER (1988) Is contiguity detection in classical conditioning a system or a cellular property? Learning in Aplysia suggests a possible molecular site. Trends Neurosci 11:128–135 27. Pankratov Y, Castro E, Miras-Portugal MT et al (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 28. Juranyi Z, Sperlagh B, Vizi ES (1999) Involvement of P2 purinoceptors and the nitric oxide pathway in [3H]purine outflow evoked by short-term hypoxia and hypoglycemia in rat hippocampal slices. Brain Res 823:183–190 29. Melani A, Turchi D, Vannucchi MG et al (2005) ATP extracellular concentrations are increased in the rat striatum during in vivo ischemia. Neurochem Int 47:442–448 30. Amadio S, D’Ambrosi N, Cavaliere F et al (2002) P2 receptor modulation and cytotoxic function in cultured CNS neurons. Neuropharmacology 42:489–501 31. Cavaliere F, D’Ambrosi N, Ciotti MT et al (2001) Glucose deprivation and chemical hypoxia: neuroprotection by P2 receptor antagonists. Neurochem Int 38:189–197 32. Volonte C, Merlo D (1996) Selected P2 purinoceptor modulators prevent glutamate-evoked cytotoxicity in cultured cerebellar granule neurons. J Neurosci Res 45:183–193 33. Volonte C, Ciotti MT, D’Ambrosi N et al (1999) Neuroprotective effects of modulators of P2 receptors in primary culture of CNS neurones. Neuropharmacology 38:1335–1342