• Geoffrey Burnstock
  • Alexei Verkhratsky


The discovery of non-adrenergic, non-cholinergic neurotransmission in the gut and bladder in the early 1960’s is described and the identification of ATP as a transmitter in these nerves in the early 1970’s. The concept of purinergic cotransmission was formulated in 1976 and it is now recognized that ATP is a cotransmitter in all nerves in the peripheral and central nervous systems. Two families of receptors to purines were recognized in 1978, P1 (adenosine) receptors and P2 receptors sensitive to ATP and ADP. Cloning of these receptors in the early 1990’s was a turning point in the acceptance of the purinergic signaling hypothesis and there are currently 4 subtypes of P1 receptors, 7 subtypes of P2X ion channel receptors, and 8 subtypes of P2Y G protein-coupled receptors. Both short-term purinergic signaling in neurotransmission, neuromodulation and neurosecretion and long-term (trophic) purinergic signalling of cell proliferation, differentiation, motility, death in development, and regeneration are recognized. There is now much known about the mechanisms underlying ATP release and extracellular breakdown by ecto-nucleotidases. The recent emphasis on purinergic neuropathology is discussed, including changes in purinergic cotransmission in development and ageing and in bladder diseases and hypertension. The involvement of neuron-glial cell interactions in various diseases of the CNS, including neuropathic pain, trauma, and ischemia, neurodegenerative diseases, neuropsychiatric disorders, and epilepsy is also considered


Amyotrophic Lateral Sclerosis P2X3 Receptor Interstitial Cystitis Purinergic Signalling Vesicular Release 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abbracchio MP, Burnstock G (1998) Purinergic signalling: pathophysiological roles. Jpn J Pharmacol 78:113–145PubMedCrossRefGoogle Scholar
  2. Bocquet N, Prado de Carvalho L, Cartaud J, Neyton J, Le Poupon C, Taly A, Grutter T, Changeux JP, Corringer PJ (2007) A prokaryotic proton-gated ion channel from the nicotinic acetylcholine receptor family. Nature 445:116–119PubMedCrossRefGoogle Scholar
  3. Bodin P, Burnstock G (2001) Purinergic signalling: ATP release. Neurochem Res 26:959–969PubMedCrossRefGoogle Scholar
  4. Bogdanov YD, Dale L, King BF, Whittock N, Burnstock G (1997) Early expression of a novel nucleotide receptor in the neural plate of Xenopus embryos. J Biol Chem 272:12583–12590PubMedCrossRefGoogle Scholar
  5. Booth IR, Edwards MD, Miller S (2003) Bacterial ion channels. Biochemistry 42:10045–10053PubMedCrossRefGoogle Scholar
  6. Booth IR, Edwards MD, Black S, Schumann U, Miller S (2007) Mechanosensitive channels in bacteria: signs of closure? Nat Rev Microbiol 5:431–440PubMedCrossRefGoogle Scholar
  7. Bradbury EJ, Burnstock G, McMahon SB (1998) The expression of P2X3 purinoceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor. Mol Cell Neurosci 12:256–268PubMedCrossRefGoogle Scholar
  8. Burnstock G, Ulrich H (2011) Purinergic signalling in embryonic and stem cell development. Cell Mol Life Sci 68:1369–1394PubMedCrossRefGoogle Scholar
  9. Burnstock G, Verkhratsky A (2009) Evolutionary origins of the purinergic signalling system. Acta Physiologica 195:415–447PubMedCrossRefGoogle Scholar
  10. Burnstock G, Verkhratsky A (2010) Long-term (trophic) purinergic signalling: purinoceptors control cell proliferation, differentiation and death. Cell Death Dis 1:e9PubMedCrossRefGoogle Scholar
  11. Burnstock G (1996) A unifying purinergic hypothesis for the initiation of pain. Lancet 347:1604–1605PubMedCrossRefGoogle Scholar
  12. Burnstock G (1999) Release of vasoactive substances from endothelial cells by shear stress and purinergic mechanosensory transduction. J Anat 194:335–342PubMedCrossRefGoogle Scholar
  13. Burnstock G (2002) Purinergic signalling and vascular cell proliferation and death. Arterioscler Thromb Vasc Biol 22:364–373PubMedCrossRefGoogle Scholar
  14. Burnstock G (2006) Pathophysiology and therapeutic potential of purinergic signaling. Pharmacol Rev 58:58–86PubMedCrossRefGoogle Scholar
  15. Burnstock G (2007) Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 87:659–797PubMedCrossRefGoogle Scholar
  16. Burnstock G (2008) Purinergic signalling and disorders of the central nervous system. Nat Rev Drug Discov 7:575–590PubMedCrossRefGoogle Scholar
  17. Burnstock G (2009) Purinergic receptors and pain. Curr Pharm Des 15:1717–1735PubMedCrossRefGoogle Scholar
  18. Burnstock G, Cocks T, Kasakov L, Wong HK (1978) Direct evidence for ATP release from non-adrenergic, non-cholinergic (“purinergic”) nerves in the guinea-pig taenia coli and bladder. Eur J Pharmacol 49:145–149PubMedCrossRefGoogle Scholar
  19. Burnstock G (2001) Purinergic signalling in lower urinary tract. In: Abbracchio MP, Williams M (eds) Handbook of experimental pharmacology, vol 151/I. Purinergic and pyrimidinergic signalling I—molecular nervous and urinogenitary system function. Springer, Berlin, pp 423–515Google Scholar
  20. Case RM, Eisner D, Gurney A, Jones O, Muallem S, Verkhratsky A (2007) Evolution of calcium homeostasis: from birth of the first cell to an omnipresent signalling system. Cell Calcium 42:345–350PubMedCrossRefGoogle Scholar
  21. Chen CC, Akopian AN, Sivilotti L, Colquhoun D, Burnstock G, Wood JN (1995) A P2X purinoceptor expressed by a subset of sensory neurons. Nature 377:428–431PubMedCrossRefGoogle Scholar
  22. Chen GQ, Cui C, Mayer ML, Gouaux E (1999) Functional characterization of a potassium-selective prokaryotic glutamate receptor. Nature 402:817–821PubMedCrossRefGoogle Scholar
  23. Cheung K–K, Chan WY, Burnstock G (2005) Expression of P2X receptors during rat brain development and their inhibitory role on motor axon outgrowth in neural tube explant cultures. Neuroscience 133:937–945PubMedCrossRefGoogle Scholar
  24. Chiu JC, Brenner ED, DeSalle R, Nitabach MN, Holmes TC, Coruzzi GM (2002) Phylogenetic and expression analysis of the glutamate-receptor-like gene family in Arabidopsis thaliana. Mol Biol Evol 19:1066–1082PubMedCrossRefGoogle Scholar
  25. Chiu J, DeSalle R, Lam HM, Meisel L, Coruzzi G (1999) Molecular evolution of glutamate receptors: a primitive signaling mechanism that existed before plants and animals diverged. Mol Biol Evol 16:826–838PubMedCrossRefGoogle Scholar
  26. Cockayne DA, Hamilton SG, Zhu Q-M, Dunn PM, Zhong Y, Novakovic S, Malmberg AB, Cain G, Berson A, Kassotakis L, Hedley L, Lachnit WG, Burnstock G, McMahon SB, Ford APDW (2000) Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 407:1011–1015PubMedCrossRefGoogle Scholar
  27. Erlinge D, Burnstock G (2008) P2 receptors in cardiovascular physiology and disease. Purinergic Signal 4:1–20PubMedCrossRefGoogle Scholar
  28. Fields D, Burnstock G (2006) Purinergic signalling in neuron-glial interactions. Nature Rev Neurosci 7:423–436CrossRefGoogle Scholar
  29. Garthwaite J (2008) Concepts of neural nitric oxide-mediated transmission. Eur J Neurosci 27:2783–2802PubMedCrossRefGoogle Scholar
  30. Höpker VH, Saffrey MJ, Burnstock G (1996) Neurite outgrowth of striatal neurons in vitro: involvement of purines in the growth promoting effect of myenteric plexus explants. Int J Dev Neurosci 14:439–451PubMedGoogle Scholar
  31. Inoue K (2007) P2 receptors and chronic pain. Purinergic Signal 3:135–144PubMedCrossRefGoogle Scholar
  32. Ponnamperuma C, Sagan C, Mariner R (1963) Synthesis of adenosine triphosphate under possible primitive Earth conditions. Nature 199:222–226PubMedCrossRefGoogle Scholar
  33. Rong W, Burnstock G (2004) Activation of ureter nociceptors by exogenous and endogenous ATP in guinea pig. Neuropharmacology 47:1093–1101PubMedCrossRefGoogle Scholar
  34. Ryten M, Hoebertz A, Burnstock G (2001) Sequential expression of three receptor subtypes for extracellular ATP in developing rat skeletal muscle. Dev Dyn 221:331–341PubMedCrossRefGoogle Scholar
  35. Sreedharan S, Shaik JH, Olszewski PK, Levine AS, Schioth HB, Fredriksson R (2011) Glutamate, aspartate and nucleotide transporters in the SLC17 family form four main phylogenetic clusters: evolution and tissue expression. BMC Genomics 11:17CrossRefGoogle Scholar
  36. Tew EMM, Anderson PN, Burnstock G (1992) Implantation of the myenteric plexus into the corpus striatum of adult rats: survival of the neurones and glia and interactions with host brain. Restor Neurol Neurosci 4:311–321PubMedGoogle Scholar
  37. Trams EG (1981) On the evolution of neurochemical transmission. Differentiation 19:125–133PubMedCrossRefGoogle Scholar
  38. Vidal M, Hicks PE, Langer SZ (1986) Differential effects of α, β-methylene ATP on responses to nerve stimulation in SHR and WKY tail arteries. Naunyn Schmiedebergs Arch Pharmacol 332:384–390PubMedCrossRefGoogle Scholar
  39. Vivian JP, Riedmaier P, Ge H, Le Nours J, Sansom FM, Wilce MC, Byres E, Dias M, Schmidberger JW, Cowan PJ, d’Apice AJ, Hartland EL, Rossjohn J, Beddoe T (2010) Crystal structure of a Legionella pneumophila ecto-triphosphate diphosphohydrolase, a structural and functional homolog of the eukaryotic NTPDases. Structure 18:228–238PubMedCrossRefGoogle Scholar
  40. Vlaskovska M, Kasakov L, Rong W, Bodin P, Bardini M, Cockayne DA, Ford APDW, Burnstock G (2001) P2X3 knockout mice reveal a major sensory role for urothelially released ATP. J Neurosci 21:5670–5677PubMedGoogle Scholar
  41. Waldrop MM (1989) Did life really start out in an RNA world? Science 246:1248–1249PubMedCrossRefGoogle Scholar
  42. Wynn G, Burnstock G (2006) Adenosine 5′-triphosphate and it’s relationship with other mediators that activate pelvic afferent neurons in the rat colorectum. Purinergic Signal 2:517–526PubMedCrossRefGoogle Scholar
  43. Zimmermann H, Mishra SK, Shukla V, Langer D, Gampe K, Grimm I, Delic J, Braun N (2007) Ecto-nucleotidases, molecular properties and functional impact. An R Acad Nac Farm 73:537–566Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Autonomic Neuroscience CentreUniversity College Medical SchoolLondonUK
  2. 2.Faculty of Life SciencesUniversity of ManchesterManchesterUK

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