Skip to main content

Introduction to Purinergic Signaling

  • Protocol
  • First Online:
Purinergic Signaling

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2041))

Abstract

Purinergic signaling was proposed in 1972, after it was demonstrated that adenosine 5′-triphosphate (ATP) was a transmitter in nonadrenergic, noncholinergic inhibitory nerves supplying the guinea-pig taenia coli. Later, ATP was identified as an excitatory cotransmitter in sympathetic and parasympathetic nerves, and it is now apparent that ATP acts as a cotransmitter in most, if not all, nerves in both the peripheral nervous system and central nervous system (CNS). ATP acts as a short-term signaling molecule in neurotransmission, neuromodulation, and neurosecretion. It also has potent, long-term (trophic) roles in cell proliferation, differentiation, and death in development and regeneration. Receptors to purines and pyrimidines have been cloned and characterized: P1 adenosine receptors (with four subtypes), P2X ionotropic nucleotide receptors (seven subtypes) and P2Y metabotropic nucleotide receptors (eight subtypes). ATP is released from different cell types by mechanical deformation, and after release, it is rapidly broken down by ectonucleotidases. Purinergic receptors were expressed early in evolution and are widely distributed on many different nonneuronal cell types as well as neurons. Purinergic signaling is involved in embryonic development and in the activities of stem cells. There is a growing understanding about the pathophysiology of purinergic signaling and there are therapeutic developments for a variety of diseases, including stroke and thrombosis, osteoporosis, pain, chronic cough, kidney failure, bladder incontinence, cystic fibrosis, dry eye, cancer, and disorders of the CNS, including Alzheimer’s, Parkinson’s. and Huntington’s disease, multiple sclerosis, epilepsy, migraine, and neuropsychiatric and mood disorders.

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

Access this chapter

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Burnstock G, Campbell G, Bennett M, Holman ME (1964) Innervation of the guinea-pig taenia coli: are there intrinsic inhibitory nerves which are distinct from sympathetic nerves? Int J Neuropharmacol 3:163–166

    Article  CAS  PubMed  Google Scholar 

  2. Burnstock G (2004) A moment of excitement. Living history series. The discovery of non-adrenergic, non-cholinergic neurotransmission. Physiol News 56:7–9

    Google Scholar 

  3. Burnstock G, Campbell G, Rand MJ (1966) The inhibitory innervation of the taenia of the guinea-pig caecum. J Physiol 182:504–526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Burnstock G (1986) The non-adrenergic non-cholinergic nervous system. Arch Int Pharmacodyn Ther 280(Suppl):1–15

    CAS  PubMed  Google Scholar 

  6. Drury AN, Szent-Györgyi A (1929) The physiological activity of adenine compounds with special reference to their action upon the mammalian heart. J Physiol Lond 68:213–237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Feldberg W, Hebb C (1948) The stimulating action of phosphate compounds on the perfused superior cervical ganglion of the cat. J Physiol 107:210–221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Holton P (1959) The liberation of adenosine triphosphate on antidromic stimulation of sensory nerves. J Physiol 145:494–504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Burnstock G, Campbell G, Satchell D, Smythe A (1970) Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non-adrenergic inhibitory nerves in the gut. Br J Pharmacol 40:668–688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  11. Ralevic V, Burnstock G (1998) Receptors for purines and pyrimidines. Pharmacol Rev 50:413–492

    CAS  PubMed  Google Scholar 

  12. Edwards FA, Gibb AJ, Colquhoun D (1992) ATP receptor-mediated synaptic currents in the central nervous system. Nature 359(6391):144–147

    Article  CAS  PubMed  Google Scholar 

  13. Evans RJ, Derkach V, Surprenant A (1992) ATP mediates fast synaptic transmission in mammalian neurons. Nature 357(6378):503–505

    Article  CAS  PubMed  Google Scholar 

  14. Lalo U, Verkhratsky A, Burnstock G, Pankratov Y (2012) P2X receptor-mediated synaptic transmission. Paper presented at the WIREs membrane transport and signaling

    Google Scholar 

  15. Burnstock G (2007) Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 87:659–797

    Article  CAS  PubMed  Google Scholar 

  16. Su C, Bevan JA, Burnstock G (1971) [3H]adenosine triphosphate: release during stimulation of enteric nerves. Science 173:337–339

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Burnstock G (1990) Co-transmission. The fifth Heymans memorial lecture – Ghent, February 17, 1990. Arch Int Pharmacodyn Ther 304:7–33

    CAS  PubMed  Google Scholar 

  19. Burnstock G (2009) Purinergic cotransmission. Exp Physiol 94(1):20–24

    Article  CAS  PubMed  Google Scholar 

  20. Burnstock G (2014) The Erasmus lecture 2012, academia Europaea. The concept of cotransmission: focus on ATP as a cotransmitter and its significance in health and disease. Eur Rev 22:1–17

    Article  Google Scholar 

  21. Westfall DP, Stitzel RE, Rowe JN (1978) The postjunctional effects and neural release of purine compounds in the guinea-pig vas deferens. Eur J Pharmacol 50:27–38

    Article  CAS  PubMed  Google Scholar 

  22. Hoyle CHV (1996) Purinergic cotransmission: parasympathetic and enteric nerves. Semin Neurosci 8:207–215

    Article  CAS  Google Scholar 

  23. Burnstock G (1993) Introduction: changing face of autonomic and sensory nerves in the circulation. In: Edvinsson L, Uddman R (eds) Vascular innervation and receptor mechanisms: new perspectives. Academic Press, USA, pp 1–22

    Google Scholar 

  24. Belai A, Burnstock G (1994) Evidence for coexistence of ATP and nitric oxide in non-adrenergic, non-cholinergic (NANC) inhibitory neurones in the rat ileum, colon and anococcygeus muscle. Cell Tissue Res 278:197–200

    Article  CAS  PubMed  Google Scholar 

  25. Silinsky EM, Hubbard JI (1973) Release of ATP from rat motor nerve terminals. Nature 243(5407):404–405

    Article  CAS  PubMed  Google Scholar 

  26. Richardson PJ, Brown SJ (1987) ATP release from affinity-purified rat cholinergic nerve terminals. J Neurochem 48(2):622–630

    Article  CAS  PubMed  Google Scholar 

  27. Sperlágh B, Sershen H, Lajtha A, Vizi ES (1998) Co-release of endogenous ATP and [3H]noradrenaline from rat hypothalamic slices: origin and modulation by α2-adrenoceptors. Neuroscience 82(2):511–520

    Article  PubMed  Google Scholar 

  28. Jo YH, Role LW (2002) Coordinate release of ATP and GABA at in vitro synapses of lateral hypothalamic neurons. J Neurosci 22(12):4794–4804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Krügel U, Schraft T, Kittner H, Kiess W, Illes P (2003) Basal and feeding-evoked dopamine release in the rat nucleus accumbens is depressed by leptin. Eur J Pharmacol 482(1–3):185–187

    Article  PubMed  CAS  Google Scholar 

  30. 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(Pt 1):115–123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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 542(Pt 2):529–536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pankratov Y, Lalo U, Krishtal O, Verkhratsky A (2003) P2X receptor-mediated excitatory synaptic currents in somatosensory cortex. Mol Cell Neurosci 24(3):842–849

    Article  CAS  PubMed  Google Scholar 

  33. Burnstock G (1996) Cotransmission with particular emphasis on the involvement of ATP. In: Fuxe K, Hökfelt T, Olson L, Ottoson D, Dahlström A, Björklund A (eds) Molecular mechanisms of neuronal communication. A tribute to Nils-Ake Hillarp, Wenner-Gren international series. Pergamon Press, Oxford, pp 67–87

    Google Scholar 

  34. Knight GE (2009) Purinergic receptors. In: Squire LR (ed) Encyclopedia of neuroscience, 4th edn. Academic Press, Oxford, pp 1245–1252

    Chapter  Google Scholar 

  35. Fields RD, Burnstock G (2006) Purinergic signaling in neuron-glia interactions. Nat Rev Neurosci 7(6):423–436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Farber K, Kettenmann H (2006) Purinergic signaling and microglia. Pflugers Arch 452(5):615–621

    Article  PubMed  CAS  Google Scholar 

  37. North RA, Verkhratsky A (2006) Purinergic transmission in the central nervous system. Pflugers Arch 452(5):479–485

    Article  CAS  PubMed  Google Scholar 

  38. Kirischuk S, Moller T, Voitenko N, Kettenmann H, Verkhratsky A (1995) ATP-induced cytoplasmic calcium mobilization in Bergmann glial cells. J Neurosci 15(12):7861–7871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kirischuk S, Scherer J, Kettenmann H, Verkhratsky A (1995) Activation of P2-purinoreceptors triggered Ca2+ release from InsP3-sensitive internal stores in mammalian oligodendrocytes. J Physiol 483(Pt 1):41–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Abbracchio MP, Burnstock G, Verkhratsky A, Zimmerman H (2009) Purinergic signaling in the nervous system: an overview. Trends Neurosci 32(1):19–29

    Article  CAS  PubMed  Google Scholar 

  41. Gourine AV, Llaudet E, Dale N, Spyer KM (2005) ATP is a mediator of chemosensory transduction in the central nervous system. Nature 436(7047):108–111

    Article  CAS  PubMed  Google Scholar 

  42. 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(21):5473–5480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Pankratov Y, Lalo U, Krishtal OA, Verkhratsky A (2009) P2X receptors and synaptic plasticity. Neuroscience 158(1):137–148

    Article  CAS  PubMed  Google Scholar 

  44. 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(7):734–749

    Article  PubMed  Google Scholar 

  45. Burnstock G, Knight GE (2004) Cellular distribution and functions of P2 receptor subtypes in different systems. Int Rev Cytol 240:31–304

    Article  CAS  PubMed  Google Scholar 

  46. Burnstock G, Wood JN (1996) Purinergic receptors: their role in nociception and primary afferent neurotransmission. Curr Opin Neurobiol 6(4):526–532

    Article  CAS  PubMed  Google Scholar 

  47. Khakh BS, North RA (2006) P2X receptors as cell-surface ATP sensors in health and disease. Nature 442(7102):527–532

    Article  CAS  PubMed  Google Scholar 

  48. Khmyz V, Maximyuk O, Teslenko V, Verkhratsky A, Krishtal O (2008) P2X3 receptor gating near normal body temperature. Pflugers Arch 456(2):339–347

    Article  CAS  PubMed  Google Scholar 

  49. Souslova V, Cesare P, Ding Y, Akopian AN, Stanfa L, Suzuki R, Carpenter K, Dickenson A, Boyce S, Hill R, Nebenuis-Oosthuizen D, Smith AJ, Kidd EJ, Wood JN (2000) Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature 407(6807):1015–1017

    Article  CAS  PubMed  Google Scholar 

  50. Cook SP, Vulchanova L, Hargreaves KM, Elde R, McCleskey EW (1997) Distinct ATP receptors on pain-sensing and stretch-sensing neurons. Nature 387(6632):505–508

    Article  CAS  PubMed  Google Scholar 

  51. Rong W, Gourine AV, Cockayne DA, Xiang Z, Ford AP, Spyer KM, Burnstock G (2003) Pivotal role of nucleotide P2X2 receptor subunit of the ATP-gated ion channel mediating ventilatory responses to hypoxia. J Neurosci 23(36):11315–11321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Erlinge D, Burnstock G (2008) P2 receptors in cardiovascular regulation and disease. Purinergic Signal 4(1):1–20

    Article  CAS  PubMed  Google Scholar 

  53. Harrington LS, Evans RJ, Wray J, Norling L, Swales KE, Vial C, Ali F, Carrier MJ, Mitchell JA (2007) Purinergic 2X1 receptors mediate endothelial dependent vasodilation to ATP. Mol Pharmacol 72(5):1132–1136

    Article  CAS  PubMed  Google Scholar 

  54. Harrington LS, Mitchell JA (2004) Novel role for P2X receptor activation in endothelium-dependent vasodilation. Br J Pharmacol 143(5):611–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Osipchuk Y, Cahalan M (1992) Cell-to-cell spread of calcium signals mediated by ATP receptors in mast cells. Nature 359(6392):241–244

    Article  CAS  PubMed  Google Scholar 

  56. Chen L, Brosnan CF (2006) Regulation of immune response by P2X7 receptor. Crit Rev Immunol 26(6):499–513

    Article  CAS  PubMed  Google Scholar 

  57. Coutinho-Silva R, Knight GE, Burnstock G (2005) Impairment of the splenic immune system in P2X2/P2X3 knockout mice. Immunobiology 209(9):661–668

    Article  CAS  PubMed  Google Scholar 

  58. Brough D, Le Feuvre RA, Wheeler RD, Solovyova N, Hilfiker S, Rothwell NJ, Verkhratsky A (2003) Ca2+ stores and Ca2+ entry differentially contribute to the release of IL-1 beta and IL-1 alpha from murine macrophages. J Immunol 170(6):3029–3036

    Article  CAS  PubMed  Google Scholar 

  59. Pelegrin P, Barroso-Gutierrez C, Surprenant A (2008) P2X7 receptor differentially couples to distinct release pathways for IL-1β in mouse macrophage. J Immunol 180(11):7147–7157

    Article  CAS  PubMed  Google Scholar 

  60. Vaughan KR, Stokes L, Prince LR, Marriott HM, Meis S, Kassack MU, Bingle CD, Sabroe I, Surprenant A, Whyte MK (2007) Inhibition of neutrophil apoptosis by ATP is mediated by the P2Y11 receptor. J Immunol 179(12):8544–8553

    Article  CAS  PubMed  Google Scholar 

  61. Idzko M, Hammad H, van Nimwegen M, Kool M, Willart MA, Muskens F, Hoogsteden HC, Luttmann W, Ferrari D, Di Virgilio F, Virchow JC Jr, Lambrecht BN (2007) Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nat Med 13(8):913–919

    Article  CAS  PubMed  Google Scholar 

  62. Hayashi T, Kawakami M, Sasaki S, Katsumata T, Mori H, Yoshida H, Nakahari T (2005) ATP regulation of ciliary beat frequency in rat tracheal and distal airway epithelium. Exp Physiol 90(4):535–544

    Article  CAS  PubMed  Google Scholar 

  63. Fu XW, Nurse CA, Cutz E (2004) Expression of functional purinergic receptors in pulmonary neuroepithelial bodies and their role in hypoxia chemotransmission. Biol Chem 385(3–4):275–284

    CAS  PubMed  Google Scholar 

  64. Mounkaila B, Marthan R, Roux E (2005) Biphasic effect of extracellular ATP on human and rat airways is due to multiple P2 purinoceptor activation. Respir Res 6:143

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Giaroni C, Knight GE, Zanetti E, Chiaravalli AM, Lecchini S, Frigo G, Burnstock G (2006) Postnatal development of P2 receptors in the murine gastrointestinal tract. Neuropharmacology 50(6):690–704

    Article  CAS  PubMed  Google Scholar 

  66. Cooke HJ, Wunderlich J, Christofi FL (2003) “The force be with you”: ATP in gut mechanosensory transduction. News Physiol Sci 18:43–49

    CAS  PubMed  Google Scholar 

  67. Van Crombruggen K, Van Nassauw L, Timmermans JP, Lefebvre RA (2007) Inhibitory purinergic P2 receptor characterisation in rat distal colon. Neuropharmacology 53(2):257–271

    Article  PubMed  CAS  Google Scholar 

  68. Furuzono S, Nakayama S, Imaizumi Y (2005) Purinergic modulation of pacemaker Ca2+ activity in interstitial cells of Cajal. Neuropharmacology 48(2):264–273

    Article  CAS  PubMed  Google Scholar 

  69. Roman RM, Feranchak AP, Salter KD, Wang Y, Fitz JG (1999) Endogenous ATP release regulates Cl− secretion in cultured human and rat biliary epithelial cells. Am J Phys 276(6 Pt 1):G1391–G1400

    CAS  Google Scholar 

  70. Dutta AK, Woo K, Doctor RB, Fitz JG, Feranchak AP (2008) Extracellular nucleotides stimulate Cl currents in biliary epithelia through receptor-mediated IP3 and Ca2+ release. Am J Physiol Gastrointest Liver Physiol 295(5):G1004–G1015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Masyuk AI, Gradilone SA, Banales JM, Huang BQ, Masyuk TV, Lee SO, Splinter PL, Stroope AJ, Larusso NF (2008) Cholangiocyte primary cilia are chemosensory organelles that detect biliary nucleotides via P2Y12 purinergic receptors. Am J Physiol Gastrointest Liver Physiol 295(4):G725–G734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Doctor RB, Matzakos T, McWilliams R, Johnson S, Feranchak AP, Fitz JG (2005) Purinergic regulation of cholangiocyte secretion: identification of a novel role for P2X receptors. Am J Physiol Gastrointest Liver Physiol 288(4):G779–G786

    Article  CAS  PubMed  Google Scholar 

  73. Liu R, Bell PD, Peti-Peterdi J, Kovacs G, Johansson A, Persson AE (2002) Purinergic receptor signaling at the basolateral membrane of macula densa cells. J Am Soc Nephrol 13(5):1145–1151

    Article  CAS  PubMed  Google Scholar 

  74. Bell PD, Lapointe JY, Sabirov R, Hayashi S, Peti-Peterdi J, Manabe K, Kovacs G, Okada Y (2003) Macula densa cell signaling involves ATP release through a maxi anion channel. Proc Natl Acad Sci U S A 100(7):4322–4327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Vallon V (2008) P2 receptors in the regulation of renal transport mechanisms. Am J Physiol Renal Physiol 294(1):F10–F27

    Article  CAS  PubMed  Google Scholar 

  76. Lee YJ, Park SH, Han HJ (2005) ATP stimulates Na+-glucose cotransporter activity via cAMP and p38 MAPK in renal proximal tubule cells. Am J Physiol Cell Physiol 289(5):C1268–C1276

    Article  CAS  PubMed  Google Scholar 

  77. Wildman SS, King BF (2008) P2X receptors: epithelial ion channels and regulators of salt and water transport. Nephron Physiol 108(3):60–67

    Article  CAS  Google Scholar 

  78. Guan Z, Osmond DA, Inscho EW (2007) P2X receptors as regulators of the renal microvasculature. Trends Pharmacol Sci 28(12):646–652

    Article  CAS  PubMed  Google Scholar 

  79. Werkstrom V, Andersson KE (2005) ATP- and adenosine-induced relaxation of the smooth muscle of the pig urethra. BJU Int 96(9):1386–1391

    Article  PubMed  CAS  Google Scholar 

  80. Ford AP, Gever JR, Nunn PA, Zhong Y, Cefalu JS, Dillon MP, Cockayne DA (2006) Purinoceptors as therapeutic targets for lower urinary tract dysfunction. Br J Pharmacol 147(Suppl 2):S132–S143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chopra B, Gever J, Barrick SR, Hanna-Mitchell AT, Beckel JM, Ford AP, Birder LA (2008) Expression and function of rat urothelial P2Y receptors. Am J Physiol Renal Physiol 294(4):F821–F829

    Article  CAS  PubMed  Google Scholar 

  82. Ruggieri MR Sr (2006) Mechanisms of disease: role of purinergic signaling in the pathophysiology of bladder dysfunction. Nat Clin Pract Urol 3(4):206–215

    Article  CAS  PubMed  Google Scholar 

  83. Gur S, Kadowitz PJ, Hellstrom WJ (2007) Purinergic (P2) receptor control of lower genitourinary tract function and new avenues for drug action: an overview. Curr Pharm Des 13(31):3236–3244

    Article  CAS  PubMed  Google Scholar 

  84. Banks FC, Knight GE, Calvert RC, Thompson CS, Morgan RJ, Burnstock G (2006) The purinergic component of human vas deferens contraction. Fertil Steril 85(4):932–939

    Article  CAS  PubMed  Google Scholar 

  85. Poletto Chaves LA, Pontelli EP, Varanda WA (2006) P2X receptors in mouse Leydig cells. Am J Physiol Cell Physiol 290(4):C1009–C1017

    Article  PubMed  CAS  Google Scholar 

  86. Lau DH, Metcalfe MJ, Mumtaz FH, Mikhailidis DP, Thompson CS (2009) Purinergic modulation of human corpus cavernosum relaxation. Int J Androl 32(2):149–155

    Article  CAS  PubMed  Google Scholar 

  87. Piper AS, Hollingsworth M (1996) P2-purinoceptors mediating spasm of the isolated uterus of the non-pregnant guinea-pig. Br J Pharmacol 117(8):1721–1729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ziganshin AU, Zaitcev AP, Khasanov AA, Shamsutdinov AF, Burnstock G (2006) Term-dependency of P2 receptor-mediated contractile responses of isolated human pregnant uterus. Eur J Obstet Gynecol Reprod Biol 129(2):128–134

    Article  CAS  PubMed  Google Scholar 

  89. Papka RE, Hafemeister J, Storey-Workley M (2005) P2X receptors in the rat uterine cervix, lumbosacral dorsal root ganglia, and spinal cord during pregnancy. Cell Tissue Res 321(1):35–44

    Article  CAS  PubMed  Google Scholar 

  90. Katugampola H, Burnstock G (2004) Purinergic signaling to rat ovarian smooth muscle: changes in P2X receptor expression during pregnancy. Cells Tissues Organs 178(1):33–47

    Article  CAS  PubMed  Google Scholar 

  91. Min K, Munarriz R, Yerxa BR, Goldstein I, Shaver SR, Cowlen MS, Traish AM (2003) Selective P2Y2 receptor agonists stimulate vaginal moisture in ovariectomized rabbits. Fertil Steril 79(2):393–398

    Article  PubMed  Google Scholar 

  92. Bardini M, Lee HY, Burnstock G (2000) Distribution of P2X receptor subtypes in the rat female reproductive tract at late pro-oestrus/early oestrus. Cell Tissue Res 299(1):105–113

    Article  CAS  PubMed  Google Scholar 

  93. Gallagher JA (2004) ATP P2 receptors and regulation of bone effector cells. J Musculoskelet Neuronal Interact 4(2):125–127

    CAS  PubMed  Google Scholar 

  94. Burnstock G, Verkhratsky A (2009) Evolutionary origins of the purinergic signaling system. Acta Physiol 195:415–447

    Article  CAS  Google Scholar 

  95. Burnstock G (1978) A basis for distinguishing two types of purinergic receptor. In: Straub RW, Bolis L (eds) Cell membrane receptors for drugs and hormones: a multidisciplinary approach. Raven Press, New York, pp 107–118

    Google Scholar 

  96. Burnstock G, Kennedy C (1985) Is there a basis for distinguishing two types of P2-purinoceptor? Gen Pharmacol 16:433–440

    Article  CAS  PubMed  Google Scholar 

  97. Brake AJ, Wagenbach MJ, Julius D (1994) New structural motif for ligand-gated ion channels defined by an ionotropic ATP receptor. Nature 371(6497):519–523

    Article  CAS  PubMed  Google Scholar 

  98. Lustig KD, Shiau AK, Brake AJ, Julius D (1993) Expression cloning of an ATP receptor from mouse neuroblastoma cells. Proc Natl Acad Sci U S A 90:5113–5117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Valera S, Hussy N, Evans RJ, Adani N, North RA, Surprenant A, Buell G (1994) A new class of ligand-gated ion channel defined by P2X receptor for extra-cellular ATP. Nature 371:516–519

    Article  CAS  PubMed  Google Scholar 

  100. Webb TE, Simon J, Krishek BJ, Bateson AN, Smart TG, King BF, Burnstock G, Barnard EA (1993) Cloning and functional expression of a brain G-protein-coupled ATP receptor. FEBS Lett 324:219–225

    Article  CAS  PubMed  Google Scholar 

  101. Dubyak GR (1991) Signal transduction by P2-purinergic receptors for extracellular ATP. Am J Respir Cell Mol Biol 4:295–300

    Article  CAS  PubMed  Google Scholar 

  102. Burnstock G (2007) Purine and pyrimidine receptors. Cell Mol Life Sci 64(12):1471–1483

    Article  CAS  PubMed  Google Scholar 

  103. Nicke A, Baumert HG, Rettinger J, Eichele A, Lambrecht G, Mutschler E, Schmalzing G (1998) P2X1 and P2X3 receptors form stable trimers: a novel structural motif of ligand-gated ion channels. EMBO J 17(11):3016–3028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Burnstock G, Verkhratsky A (2012) Purinergic signaling and the nervous system. Springer, Heidelberg/Berlin, pp 1–715

    Book  Google Scholar 

  105. Agboh KC, Webb TE, Evans RJ, Ennion SJ (2004) Functional characterization of a P2X receptor from Schistosoma mansoni. J Biol Chem 279(40):41650–41657

    Article  CAS  PubMed  Google Scholar 

  106. Fountain SJ, Parkinson K, Young MT, Cao L, Thompson CR, North RA (2007) An intracellular P2X receptor required for osmoregulation in Dictyostelium discoideum. Nature 448(7150):200–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Demidchik V, Nichols C, Oliynyk M, Dark A, Glover BJ, Davies JM (2003) Is ATP a signaling agent in plants? Plant Physiol 133(2):456–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Jeter CR, Roux SJ (2006) Plant responses to extracellular nucleotides: cellular processes and biological effects. Purinergic Signal 2(3):443–449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kim SY, Sivaguru M, Stacey G (2006) Extracellular ATP in plants. Visualization, localization, and analysis of physiological significance in growth and signaling. Plant Physiol 142(3):984–992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Verkhratsky A, Burnstock G (2014) Biology of purinergic signaling: its ancient evolutionary roots, its omnipresence and its multiple functional significance. Bioessays 36(7):697–705

    Article  CAS  PubMed  Google Scholar 

  111. Abbracchio MP, Burnstock G (1998) Purinergic signaling: pathophysiological roles. Jpn J Pharmacol 78:113–145

    Article  CAS  PubMed  Google Scholar 

  112. Burnstock G (2016) Short- and long-term (trophic) purinergic signaling. Philos Trans R Soc Lond B Biol Sci 371(1700):20150422

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Burnstock G, Verkhratsky A (2010) Long-term (trophic) purinergic signaling: purinoceptors control cell proliferation, differentiation and death. Cell Death Dis 1:e9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Burnstock G (2002) Purinergic signaling and vascular cell proliferation and death. Arterioscler Thromb Vasc Biol 22(3):364–373

    Article  PubMed  CAS  Google Scholar 

  115. Burnstock G (2008) Dual control of vascular tone and remodelling by ATP released from nerves and endothelial cells. Pharmacol Rep 60(1):12–20

    CAS  PubMed  Google Scholar 

  116. Erlinge D, Burnstock G (2008) P2 receptors in cardiovascular physiology and disease. Purinergic Signal 4(1):1–20

    Article  CAS  PubMed  Google Scholar 

  117. Bodin P, Burnstock G (2001) Purinergic signaling: ATP release. Neurochem Res 26(8–9):959–969

    Article  CAS  PubMed  Google Scholar 

  118. Burnstock G, Knight GE (2017) Cell culture: complications due to mechanical release of ATP and activation of purinoceptors. Cell Tissue Res 370:1–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Moriyama Y, Hiasa M, Sakamoto S, Omote H, Nomura M (2017) Vesicular nucleotide transporter (VNUT): appearance of an actress on the stage of purinergic signaling. Purinergic Signal 13(3):387–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Dahl G (2015) ATP release through pannexon channels. Philos Trans R Soc Lond Ser B Biol Sci 370:20140191

    Article  CAS  Google Scholar 

  121. Lazarowski ER, Sesma JI, Seminario-Vidal L, Kreda SM (2011) Molecular mechanisms of purine and pyrimidine nucleotide release. Adv Pharmacol 61:221–261

    Article  CAS  PubMed  Google Scholar 

  122. Yegutkin GG (2014) Enzymes involved in metabolism of extracellular nucleotides and nucleosides: functional implications and measurement of activities. Crit Rev Biochem Mol Biol 49(6):473–497

    Article  CAS  PubMed  Google Scholar 

  123. 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 73:537–566

    CAS  Google Scholar 

  124. Fields D, Burnstock G (2006) Purinergic signaling in neuron-glial interactions. Nat Rev Neurosci 7(6):423–436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Verkhratsky A, Krishtal OA, Burnstock G (2009) Purinoceptors in neuroglia. Mol Neurobiol 39(3):190–208

    Article  CAS  PubMed  Google Scholar 

  126. Burnstock G (2006) Pathophysiology and therapeutic potential of purinergic signaling. Pharmacol Rev 58(1):58–86

    Article  CAS  PubMed  Google Scholar 

  127. Burnstock G, Dale N (2015) Purinergic signaling in development and ageing. Purinergic Signal 11(3):277–305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. 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(19):12583–12590

    Article  CAS  PubMed  Google Scholar 

  129. Ryten M, Hoebertz A, Burnstock G (2001) Sequential expression of three receptor subtypes for extracellular ATP in developing rat skeletal muscle. Dev Dyn 221:331–341

    Article  CAS  PubMed  Google Scholar 

  130. 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(4):937–945

    Article  CAS  PubMed  Google Scholar 

  131. 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 4:311–321

    CAS  PubMed  Google Scholar 

  132. 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(4):439–451

    Article  PubMed  Google Scholar 

  133. Burnstock G, Ulrich H (2011) Purinergic signaling in embryonic and stem cell development. Cell Mol Life Sci 68:1369–1394

    Article  CAS  PubMed  Google Scholar 

  134. Grimm I, Messemer N, Stanke M, Gachet C, Zimmermann H (2009) Coordinate pathways for nucleotide and EGF signaling in cultured adult neural progenitor cells. J Cell Sci 122(Pt 14):2524–2533

    Article  CAS  PubMed  Google Scholar 

  135. Burnstock G (2013) Purinergic signaling in the lower urinary tract. Acta Physiol 207(1):40–52

    Article  CAS  Google Scholar 

  136. Burnstock G (2014) Purinergic signaling in the urinary tract in health and disease. Purinergic Signal 10(1):103–155

    Article  CAS  PubMed  Google Scholar 

  137. 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 49:145–149

    Article  CAS  PubMed  Google Scholar 

  138. Burnstock G (2001) Purinergic signaling in lower urinary tract. In: Abbracchio MP, Williams M (eds) Handbook of experimental pharmacology, vol 151/I. Purinergic and pyrimidinergic signaling: I – Molecular, nervous and urinogenitary system function, vol 151/I. Handbook of experimental pharmacology. Springer-Verlag, Berlin, pp 423–515

    Chapter  Google Scholar 

  139. 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 332:384–390

    Article  CAS  PubMed  Google Scholar 

  140. Boeynaems JM, Communi D, Gonzalez NS, Robaye B (2005) Overview of the P2 receptors. Semin Thromb Hemost 31(2):139–149

    Article  CAS  PubMed  Google Scholar 

  141. Burnstock G, Ralevic V (2014) Purinergic signaling and blood vessels in health and disease. Pharmacol Rev 66(1):102–192

    Article  PubMed  CAS  Google Scholar 

  142. Thachil J (2016) Antiplatelet therapy – a summary for the general physicians. Clin Med 16(2):152–160

    Article  Google Scholar 

  143. Burnstock G (2008) Commentary. Purinergic receptors as future targets for treatment of functional GI disorders. Gut 57(9):1193–1194

    Article  PubMed  Google Scholar 

  144. Burnstock G, Jacobson KA, Christofi FL (2017) Purinergic drug targets for gastrointestinal disorders. Curr Opin Pharmacol 37:131–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Dal Ben D, Antonioli L, Lambertucci C, Fornai M, Blandizzi C, Volpini R (2018) Purinergic ligands as potential therapeutic tools for the treatment of inflammation-related intestinal diseases. Front Pharmacol 9:212

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Longhi MS, Moss A, Jiang ZG, Robson SC (2017) Purinergic signaling during intestinal inflammation. J Mol Med (Berl) 95(9):915–925

    Article  CAS  Google Scholar 

  147. Yerxa BR (2001) Therapeutic use of nucleotides in respiratory and ophthalmic diseases. Drug Dev Res 52:196–201

    Article  CAS  Google Scholar 

  148. Burnstock G, Di Virgilio F (2013) Purinergic signaling in cancer. Purinergic Signal 9:491–540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Di Virgilio F, Sarti AC, Falzoni S, De ME, Adinolfi E (2018) Extracellular ATP and P2 purinergic signaling in the tumour microenvironment. Nat Rev Cancer 18(10):601–618

    Article  PubMed  CAS  Google Scholar 

  150. Shabbir M, Burnstock G (2009) Purinergic receptor-mediated effects of ATP in urogenital malignant diseases. Int J Urol 16(2):143–150

    Article  CAS  PubMed  Google Scholar 

  151. White N, Burnstock G (2006) P2 receptors and cancer. Trends Pharmacol Sci 27(4):211–217

    Article  CAS  PubMed  Google Scholar 

  152. Burnstock G (2017) Purinergic signaling: therapeutic developments. Front Pharmacol 8:661

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. 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(4–5):256–268

    Article  CAS  PubMed  Google Scholar 

  154. Chen CC, Akopian AN, Sivilotti L, Colquhoun D, Burnstock G, Wood JN (1995) A P2X purinoceptor expressed by a subset of sensory neurons. Nature 377:428–431

    Article  CAS  PubMed  Google Scholar 

  155. Burnstock G (1996) A unifying purinergic hypothesis for the initiation of pain. Lancet 347:1604–1605

    Article  CAS  PubMed  Google Scholar 

  156. Burnstock G (1999) Release of vasoactive substances from endothelial cells by shear stress and purinergic mechanosensory transduction. J Anat 194(3):335–342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Burnstock G (2009) Purinergic mechanosensory transduction and visceral pain. Mol Pain 5:69

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. 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(15):5670–5677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Rong W, Burnstock G (2004) Activation of ureter nociceptors by exogenous and endogenous ATP in guinea pig. Neuropharmacology 47(7):1093–1101

    Article  CAS  PubMed  Google Scholar 

  160. 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 2:517–526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Rong W, Burnstock G, Spyer KM (2000) P2X purinoceptor-mediated excitation of trigeminal lingual nerve terminals in an in vitro intra-arterially perfused rat tongue preparation. J Physiol 524(Pt 3):891–902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. 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(6807):1011–1015

    Article  CAS  PubMed  Google Scholar 

  163. Bele T, Fabbretti E (2015) P2X receptors, sensory neurons and pain. Curr Med Chem 22(7):845–850

    Article  CAS  PubMed  Google Scholar 

  164. Burnstock G (2009) Purinergic receptors and pain. Curr Pharm Des 15(15):1717–1735

    Article  CAS  PubMed  Google Scholar 

  165. Burnstock G (2016) Purinergic receptors and pain – an update. In: Front Med Chem, vol 9, pp 3–55

    Chapter  Google Scholar 

  166. Inoue K (2007) P2 receptors and chronic pain. Purinergic Signal 3:135–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Tsuda M, Inoue K (2016) Neuron-microglia interaction by purinergic signaling in neuropathic pain following neurodegeneration. Neuropharmacology 104:76–81

    Article  CAS  PubMed  Google Scholar 

  168. Burnstock G (2008) Purinergic signaling and disorders of the central nervous system. Nat Rev Drug Discov 7:575–590

    Article  CAS  PubMed  Google Scholar 

  169. Cheffer A, Castillo ARG, Corrêa-Velloso J, Gonçalves MCB, Naaldijk Y, Nascimento I, Burnstock G, Ulrich H (2017) Purinergic system in psychiatric diseases. Mol Psychiatry 23(1):94–106

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Geoffrey Burnstock .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Burnstock, G. (2020). Introduction to Purinergic Signaling. In: Pelegrín, P. (eds) Purinergic Signaling. Methods in Molecular Biology, vol 2041. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9717-6_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-9717-6_1

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-9716-9

  • Online ISBN: 978-1-4939-9717-6

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics