Abstract
The article will begin with the discovery of purinergic inhibitory neuromuscular transmission in the 1960s/1970s, the proposal for purinergic cotransmission in 1976 and the recognition that sympathetic nerves release adenosine 5′-triphosphate (ATP), noradrenaline and neuropeptide Y, while non-adrenergic, non-cholinergic inhibitory nerve cotransmitters are ATP, nitric oxide and vasoactive intestinal polypeptide in variable proportions in different regions of the gut. Later, purinergic synaptic transmission in the myenteric and submucosal plexuses was established and purinergic receptors expressed by both glial and interstitial cells. The focus will then be on purinergic mechanosensory transduction involving release of ATP from mucosal epithelial cells during distension to activate P2X3 receptors on submucosal sensory nerve endings. The responses of low threshold fibres mediate enteric reflex activity via intrinsic sensory nerves, while high threshold fibres initiate pain via extrinsic sensory nerves. Finally, the involvement of purinergic signalling in an animal model of colitis will be presented, showing that during distension there is increased ATP release, increased P2X3 receptor expression on calcitonin gene-related peptide-labelled sensory neurons and increased sensory nerve activity.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Antonioli L, Fornai M, Blandizzi C, Salvadorini C, Colucci R, Breschi MC, Del Taca M (2005) The inhibitory effects of adenosine on enteric neuromuscular activity are decreased in inflammed colonic tissues. Gastroenterology 128:A273
Antonioli L, Fornai M, Colucci R, Ghisu N, Blandizzi C, Del Tacca M (2006) A2a receptors mediate inhibitory effects of adenosine on colonic motility in the presence of experimental colitis. Inflamm Bowel Dis 12:117–122
Antonioli L, Fornai M, Colucci R, Ghisu N, Da SF, Natale G, Kastsiuchenka O, Duranti E, Virdis A, Vassalle C, La MC, Mugnaini L, Breschi MC, Blandizzi C, Del Taca M (2007) Inhibition of adenosine deaminase attenuates inflammation in experimental colitis. J Pharmacol Exp Ther 322:435–442
Antonioli L, Fornai M, Colucci R, Awwad O, Ghisu N, Tuccori M, Da SF, La Motta C, Natale G, Duranti E, Virdis A, Blandizzi C (2010) The blockade of adenosine deaminase ameliorates chronic experimental colitis through the recruitment of adenosine A2A and A3 receptors. J Pharmacol Exp Ther 335:434–442
Antonioli L, Fornai M, Colucci R, Awwad O, Ghisu N, Tuccori M, Del Tacca M, Blandizzi C (2011) Differential recruitment of high affinity A1 and A2A adenosine receptors in the control of colonic neuromuscular function in experimental colitis. Eur J Pharmacol 650:639–649
Balestra B, Vicini R, Cremon C, Zecchi L, Dothel G, Vasina V, De GR, Paccapelo A, Pastoris O, Stanghellini V, Corinaldesi R, De Ponti F, Tonini M, Barbara G (2012) Colonic mucosal mediators from patients with irritable bowel syndrome excite enteric cholinergic motor neurons. Neurogastroenterol Motil 24:1118-e570
Barajas-López C, Espinosa-Luna R, Gerzanich V (1994) ATP closes a potassium and opens a cationic conductance through different receptors in neurons of guinea pig submucous plexus. J Pharmacol Exp Ther 268:1397–1402
Barajas-López C, Huizinga JD, Collins SM, Gerzanich V, Espinosa-Luna R, Peres AL (1996) P2x-purinoceptors of myenteric neurones from the guinea-pig ileum and their unusual pharmacological properties. Br J Pharmacol 119:1541–1548
Barajas-López C, Espinosa-Luna R, Zhu Y (1998) Functional interactions between nicotinic and P2X channels in short-term cultures of guinea-pig submucosal neurons. J Physiol 513:671–683
Barajas-López C, Espinosa-Luna R, Christofi FL (2000) Changes in intracellular Ca2+ by activation of P2 receptors in submucosal neurons in short-term cultures. Eur J Pharmacol 409:243–257
Barajas-López C, Montaño LM, Espinosa-Luna R (2002) Inhibitory interactions between 5-HT3 and P2X channels in submucosal neurons. Am J Physiol Gastrointest Liver Physiol 283:G1238–G1248
Bertrand PP (2003) ATP and sensory transduction in the enteric nervous system. Neuroscientist 9:243–260
Bertrand PP (2004) Bursts of recurrent excitation in the activation of intrinsic sensory neurons of the intestine. Neuroscience 128:51–63
Bertrand PP, Bornstein JC (2002) ATP as a putative sensory mediator: activation of intrinsic sensory neurons of the myenteric plexus via P2X receptors. J Neurosci 22:4767–4775
Beyazit Y, Koklu S, Tas A, Purnak T, Sayilir A, Kurt M, Turhan T, Celik T, Suvak B, Torun S, Akbal E (2012) Serum adenosine deaminase activity as a predictor of disease severity in ulcerative colitis. J Crohns Colitis 6:102–107
Bian XC, Bertrand PP, Bornstein JC (2000) Descending inhibitory reflexes involve P2X receptor-mediated transmission from interneurons to motor neurons in guinea-pig ileum. J Physiol 528:551–560
Bian X, Ren J, DeVries M, Schnegelsberg B, Cockayne DA, Ford AP, Galligan JJ (2003) Peristalsis is impaired in the small intestine of mice lacking the P2X3 subunit. J Physiol 551:309–322
Bornstein JC (2008) Purinergic mechanisms in the control of gastrointestinal motility. Purinergic Signal 4:197–212
Bornstein JC, Costa M, Grider JR (2004) Enteric motor and interneuronal circuits controlling motility. Neurogastroenterol Motil 16(Suppl 1):34–38
Bours MJ, Troost FJ, Brummer RJ, Bast A, Dagnelie PC (2007) Local effect of adenosine 5′-triphosphate on indomethacin-induced permeability changes in the human small intestine. Eur J Gastroenterol Hepatol 19:245–250
Brierley SM, Carter R, Jones W III, Xu L, Robinson DR, Hicks GA, Gebhart GF, Blackshaw LA (2005) Differential chemosensory function and receptor expression of splanchnic and pelvic colonic afferents in mice. J Physiol 567:267–281
Bülbring E, Tomita T (1967) Properties of the inhibitory potential of smooth muscle as observed in the response to field stimulation of the guinea-pig taenia coli. J Physiol 189:299–315
Burnstock G (1969) Evolution of the autonomic innervation of visceral and cardiovascular systems in vertebrates. Pharmacol Rev 21:247–324
Burnstock G (1972) Purinergic nerves. Pharmacol Rev 24:509–581
Burnstock G (1976) Do some nerve cells release more than one transmitter? Neuroscience 1:239–248
Burnstock G (1993) Physiological and pathological roles of purines: an update. Drug Dev Res 28:195–206
Burnstock G (1999) Release of vasoactive substances from endothelial cells by shear stress and purinergic mechanosensory transduction. J Anat 194:335–342
Burnstock G (2001a) Purinergic signalling in gut. In: Abbracchio MP, Williams M (eds) Handbook of experimental pharmacology, vol 151/II. Purinergic and pyrimidinergic signalling II – cardiovascular, respiratory, immune, metabolic and gastrointestinal tract function. Springer, Berlin, pp 141–238
Burnstock G (2001b) Purine-mediated signalling in pain and visceral perception. Trends Pharmacol Sci 22:182–188
Burnstock G (2004) A moment of excitement. Living history series. The discovery of non-adrenergic, non-cholinergic neurotransmission. Physiol News 56:7–9
Burnstock G (2007a) Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 87:659–797
Burnstock G (2007b) Purine and pyrimidine receptors. Cell Mol Life Sci 64:1471–1483
Burnstock G (2008a) The journey to establish purinergic signalling in the gut. Neurogastroenterol Motil 20:8–19
Burnstock G (2008b) Commentary. Purinergic receptors as future targets for treatment of functional GI disorders. Gut 57:1193–1194
Burnstock G (2009) Purinergic mechanosensory transduction and visceral pain. Mol Pain 5:69
Burnstock G (2011) Purinergic signaling in the gastrointestinal tract. World J Gastrointest Pathophysiol 2:31–34
Burnstock G (2012a) The Gaddum Lecture. Discovery of purinergic signalling, the initial resistance and current explosion of interest. Br J Pharmacol 167:238–255
Burnstock G (2012b) P2X receptors in the gut. WIREs Membr Transp Signaling 1:269–279
Burnstock G (2014) Purinergic signalling in the gastrointestinal tract and related organs in health and disease. Purinergic Signal 10(1):3–50
Burnstock G, Knight GE (2004) Cellular distribution and functions of P2 receptor subtypes in different systems. Int Rev Cytol 240:31–304
Burnstock G, Lavin S (2002) Interstitial cells of Cajal and purinergic signalling. Auton Neurosci 97:68–72
Burnstock G, Straub RW (1958) A method for studying the effects of ions and drugs on the resting and action potentials in smooth muscle with external electrodes. J Physiol 140:156–167
Burnstock G, Verkhratsky A (2012) Purinergic signalling and the nervous system. Springer, Heidelberg/Berlin
Burnstock G, Campbell G, Bennett M, Holman ME (1963) The effects of drugs on the transmission of inhibition from autonomic nerves to the smooth muscle of the guinea pig taenia coli. Biochem Pharmacol 12:134–135
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
Burnstock G, Campbell G, Rand MJ (1966) The inhibitory innervation of the taenia of the guinea-pig caecum. J Physiol 182:504–526
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
Burnstock G, Fredholm BB, North RA, Verkhratsky A (2010) The birth and postnatal development of purinergic signalling. Acta Physiol (Oxf) 199:93–147
Castelucci P, Robbins HL, Poole DP, Furness JB (2002) The distribution of purine P2X2 receptors in the guinea-pig enteric nervous system. Histochem Cell Biol 117:415–422
Cesaro A, Brest P, Hofman V, Hébuterne X, Wildman S, Ferrua B, Marchetti S, Doglio A, Vouret-Craviari V, Galland F, Naquet P, Mograbi B, Unwin R, Hofman P (2010) Amplification loop of the inflammatory process is induced by P2X7R activation in intestinal epithelial cells in response to neutrophil transepithelial migration. Am J Physiol Gastrointest Liver Physiol 299:G32–G42
Chen H, Redelman D, Ro S, Ward SM, Ördög T, Sanders KM (2007) Selective labeling and isolation of functional classes of interstitial cells of Cajal of human and murine small intestine. Am J Physiol Cell Physiol 292:C497–C507
Christofi FL (2008) Purinergic receptors and gastrointestinal secretomotor function. Purinergic Signal 4:213–236
Christofi FL, Wood JD (1993) Endogenously released adenosine acts at A1 receptors to suppress slow excitatory transmission (slow EPSP) and enhance slow inhibitory transmission (slow IPSP) in the myenteric plexus of guinea-pig small intestine. Gastroenterology 104:A490
Clark SR, Costa M, Tonini M, Brookes SJ (1996) Purinergic transmission is involved in a descending excitatory reflex in the guinea-pig small intestine. Proc Aust Neurosci Soc 7:176
Colgan SP, Fennimore B, Ehrentraut SF (2013) Adenosine and gastrointestinal inflammation. J Mol Med (Berl) 91:157–164
Damen R, Haugen M, Svejda B, Alaimo D, Brenna O, Pfragner R, Gustafsson BI, Kidd M (2013) The stimulatory adenosine receptor ADORA2B regulates serotonin (5-HT) synthesis and release in oxygen-depleted EC cells in inflammatory bowel disease. PLoS One 8, e62607
Dang K, Bielfeldt K, Lamb K, Gebhart GF (2005) Gastric ulcers evoke hyperexcitability and enhance P2X receptor function in rat gastric sensory neurons. J Neurophysiol 93:3112–3119
de Campos NE, Marques-da-Silva C, Corrêa G, Castelo-Branco MT, de Souza HS, Coutinho-Silva R (2012) Characterizing the presence and sensitivity of the P2X7 receptor in different compartments of the gut. J Innate Immun 4:529–541
De Man JG, De Winter BY, Seerden TC, De Schepper HU, Herman AG, Pelckmans PA (2003) Functional evidence that ATP or a related purine is an inhibitory NANC neurotransmitter in the mouse jejunum: study on the identity of P2X and P2Y purinoceptors involved. Br J Pharmacol 140:1108–1116
Decker DA, Galligan JJ (2010) Molecular mechanisms of cross-inhibition between nicotinic acetylcholine receptors and P2X receptors in myenteric neurons and HEK-293 cells. Neurogastroenterol Motil 22:901–908, e235
Degagné É, Turgeon N, Moore-Gagné J, Asselin C, Gendron FP (2012) P2Y2 receptor expression is regulated by C/EBPβ during inflammation in intestinal epithelial cells. FEBS J 279:2957–2965
Donnelly-Roberts D, McGaraughty S, Shieh CC, Honore P, Jarvis MF (2008) Painful purinergic receptors. J Pharmacol Exp Ther 324:409–415
Drury AN, Szent-Györgyi A (1929) The physiological activity of adenine compounds with special reference to their action upon the mammalian heart. J Physiol 68:213–237
Dubyak GR, El Moatassim C (1993) Signal transduction via P2-purinergic receptors for extracellular ATP and other nucleotides. Am J Physiol 265:C577–C606
Eccles JC (1964) The Physiology of Synapses. Springer, Berlin, pp 1–316
El-Tayeb A, Michael S, Abdelrahman A, Behrenswerth A, Gollos S, Nieber K, Müller CE (2011) Development of polar adenosine A2A receptor agonists for inflammatory bowel disease: synergism with A2B antagonists. ACS Med Chem Lett 2:890–895
Estrela AB, Abraham WR (2011) Adenosine in the inflamed gut: a Janus faced compound. Curr Med Chem 18:2791–2815
Evans RJ, Surprenant A (1992) Vasoconstriction of guinea-pig submucosal arterioles following sympathetic nerve stimulation is mediated by the release of ATP. Br J Pharmacol 106:242–249
Fan J, Yu L, Zhang W, Zhao T, Yu Y, Gao J, Zou D, Ni X, Ma B, Burnstock G (2009) Estrogen altered visceromotor reflex and P2X3 mRNA expression in a rat model of colitis. Steroids 74:956–963
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
Furness JB, Morris JL, Gibbins IL, Costa M (1989) Chemical coding of neurons and plurichemical transmission. Annu Rev Pharmacol Toxicol 29:289–306
Furness JB, Jones C, Nurgali K, Clerc N (2004a) Intrinsic primary afferent neurons and nerve circuits within the intestine. Prog Neurobiol 72:143–164
Furness JB, Robbins HL, **ao J, Stebbing MJ, Nurgali K (2004b) Projections and chemistry of Dogiel type II neurons in the mouse colon. Cell Tissue Res 317:1–12
Furuya S, Furuya K (2013) Roles of substance P and ATP in the subepithelial fibroblasts of rat intestinal villi. Int Rev Cell Mol Biol 304:133–189
Furuzono S, Nakayama S, Imaizumi Y (2005) Purinergic modulation of pacemaker Ca2+ activity in interstitial cells of Cajal. Neuropharmacology 48:264–273
Gade AR, Akbarali HI (2013) Electrophysiological characterization of purinergic receptors in mouse enteric neuron-glia culture. FASEB J 27:1093.24
Gallego D, Vanden Berghe P, Farré R, Tack J, Jiménez M (2008) P2Y1 receptors mediate inhibitory neuromuscular transmission and enteric neuronal activation in small intestine. Neurogastroenterol Motil 20:159–168
Gallego D, Gil V, Martínez-Cutillas M, Mañe N, Martín MT, Jiménez M (2012) Purinergic neuromuscular transmission is absent in the colon of P2Y1 knocked out mice. J Physiol 590:1943–1956
Galligan JJ (2002) Pharmacology of synaptic transmission in the enteric nervous system. Curr Opin Pharmacol 2:623–629
Galligan JJ (2004) Enteric P2X receptors as potential targets for drug treatment of the irritable bowel syndrome. Br J Pharmacol 141:1294–1302
Galligan JJ, North RA (2004) Pharmacology and function of nicotinic acetylcholine and P2X receptors in the enteric nervous system. Neurogastroenterol Motil 16(Suppl 1):64–70
Galligan JJ, LePard KJ, Schneider DA, Zhou X (2000) Multiple mechanisms of fast excitatory synaptic transmission in the enteric nervous system. J Auton Nerv Syst 81:97–103
Gao N, Hu HZ, Zhu MX, Fang X, Liu S, Gao C, Wood JD (2006) The P2Y1 purinergic receptor expressed by enteric neurones in guinea-pig intestine. Neurogastroenterol Motil 18:316–323
Gessi S, Merighi S, Varani K, Leung E, Mac Lennan S, Borea PA (2008) The A3 adenosine receptor: an enigmatic player in cell biology. Pharmacol Ther 117:123–140
Gever J, Cockayne DA, Dillon MP, Burnstock G, Ford APDW (2006) Pharmacology of P2X channels. Pflugers Arch 452:513–537
Giaroni C, Knight GE, Ruan H-Z, Glass R, Bardini M, Lecchini S, Frigo G, Burnstock G (2002) P2 receptors in the murine gastrointestinal tract. Neuropharmacology 43:1313–1323
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 50:690–704
Glushakov AV, Melishchuk AI, Skok VI (1996) ATP-induced currents in submucous plexus neurons of the guinea-pig small intestine. Neurophysiology 28:77–85
Grbic DM, Degagné E, Langlois C, Dupuis AA, Gendron FP (2008) Intestinal inflammation increases the expression of the P2Y6 receptor on epithelial cells and the release of CXC chemokine ligand 8 by UDP. J Immunol 180:2659–2668
Grbic DM, Degagné É, Larriveé JF, Bilodeau MS, Vinette V, Arguin G, Stankova J, Gendron FP (2012) P2Y6 receptor contributes to neutrophil recruitment to inflamed intestinal mucosa by increasing CXC chemokine ligand 8 expression in an AP-1-dependent manner in epithelial cells. Inflamm Bowel Dis 18:1456–1469
Gröschel-Stewart U, Bardini M, Robson T, Burnstock G (1999) P2X receptors in the rat duodenal villus. Cell Tissue Res 297:111–117
Gulbransen BD, Sharkey KA (2009) Purinergic neuron-to-glia signaling in the enteric nervous system. Gastroenterology 136:1349–1358
Gulbransen BD, Bains JS, Sharkey KA (2010) Enteric glia are targets of the sympathetic innervation of the myenteric plexus in the guinea pig distal colon. J Neurosci 30:6801–6809
Gulbransen BD, Bashashati M, Hirota SA, Gui X, Roberts JA, MacDonald JA, Muruve DA, McKay DM, Beck PL, Mawe GM, Thompson RJ, Sharkey KA (2012) Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitis. Nat Med 18:600–604
Guzman J, Yu JG, Suntres Z, Bozarov A, Cooke H, Javed N, Auer H, Palatini J, Hassanain HH, Cardounel AJ, Javed A, Grants I, Wunderlich JE, Christofi FL (2006) ADOA3R as a therapeutic target in experimental colitis: proof by validated high-density oligonucleotide microarray analysis. Inflamm Bowel Dis 12:766–789
Holton P (1959) The liberation of adenosine triphosphate on antidromic stimulation of sensory nerves. J Physiol 145:494–504
Holzer P (2004) Gastrointestinal pain in functional bowel disorders: sensory neurons as novel drug targets. Expert Opin Ther Targets 8:107–123
Holzer P (2006) Efferent-like roles of afferent neurons in the gut: blood flow regulation and tissue protection. Auton Neurosci 125:70–75
Hoyle CHV (1992) Transmission: purines. In: Burnstock G, Hoyle CHV (eds) The autonomic nervous system. Autonomic neuroeffector mechanisms. Harwood Academic Publishers, Chur, pp 367–407
Hoyle CHV, Burnstock G (1989) Neuromuscular transmission in the gastrointestinal tract. In: Wood JD (ed) Handbook of physiology, Section 6: The gastrointestinal system, Vol. I: Motility and circulation. American Physiological Society, Bethesda, MD, pp 435–464
Hu HZ, Gao N, Zhu MX, Liu S, Ren J, Gao C, **a Y, Wood JD (2003) Slow excitatory synaptic transmission mediated by P2Y1 receptors in the guinea-pig enteric nervous system. J Physiol 550:493–504
Ivancheva C, Rahamimoff R, Radomirov R (2001) Apamin-sensitive nitric oxide- and ATP-mediated motor effects on the guinea pig small intestine. Gen Physiol Biophys 20:97–108
Johnson CR, Hourani SMO (1994) Contractile effects of uridine 5′-triphosphate in the rat duodenum. Br J Pharmacol 113:1191–1196
Johnson CR, Charlton SJ, Hourani SMO (1996) Responses of the longitudinal muscle and the muscularis mucosae of the rat duodenum to adenine and uracil nucleotides. Br J Pharmacol 117:823–830
Kamiji T, Morita K, Katayama Y (1994) ATP regulates synaptic transmission by pre- and postsynaptic mechanisms in guinea-pig myenteric neurons. Neuroscience 59:165–174
Karanjia R, García-Hernandez LM, Miranda-Morales M, Somani N, Espinosa-Luna R, Montaño LM, Barajas-López C (2006) Cross-inhibitory interactions between GABAA and P2X channels in myenteric neurones. Eur J Neurosci 23:3259–3268
Katayama Y, Morita K (1989) Adenosine 5′-triphosphate modulates membrane potassium conductance in guinea-pig myenteric neurones. J Physiol 408:373–390
Keating C, Pelegrin P, Martinez CM, Grundy D (2011) P2X7 receptor-dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome. J Immunol 187:1467–1474
Kimball BC, Mulholland MW (1995) Neuroligands evoke calcium signaling in cultured myenteric neurons. Surgery 118:162–169
Kimball BC, Mulholland MW (1996) Enteric glia exhibit P2U receptors that increase cytosolic calcium by a phospholipase C-dependent mechanism. J Neurochem 66:604–612
King BF, Townsend-Nicholson A (2008) Involvement of P2Y1 and P2Y11 purinoceptors in parasympathetic inhibition of colonic smooth muscle. J Pharmacol Exp Ther 324:1055–1063
Kirkup AJ, Brunsden AM, Grundy D (2001) Receptors and transmission in the brain-gut axis: potential for novel therapies. I. Receptors on visceral afferents. Am J Physiol Gastrointest Liver Physiol 280:G787–G794
Kolachala V, Asamoah V, Wang L, Obertone TS, Ziegler TR, Merlin D, Sitaraman SV (2005) TNF-α upregulates adenosine 2b (A2b) receptor expression and signaling in intestinal epithelial cells: a basis for A2bR overexpression in colitis. Cell Mol Life Sci 62:2647–2657
Kolachala VL, Ruble BK, Vijay-Kumar M, Wang L, Mwangi S, Figler HE, Figler RA, Srinivasan S, Gewirtz AT, Linden J, Merlin D, Sitaraman SV (2008a) Blockade of adenosine A2B receptors ameliorates murine colitis. Br J Pharmacol 155:127–137
Kolachala VL, Vijay-Kumar M, Dalmasso G, Yang D, Linden J, Wang L, Gewirtz A, Ravid K, Merlin D, Sitaraman SV (2008b) A2B adenosine receptor gene deletion attenuates murine colitis. Gastroenterology 135:861–870
Kolachala VL, Bajaj R, Chalasani M, Sitaraman SV (2008c) Purinergic receptors in gastrointestinal inflammation. Am J Physiol Gastrointest Liver Physiol 294:G401–G410
Künzli BM, Berberat PO, Dwyer K, Deaglio S, Csizmadia E, Cowan P, d’Apice A, Moore G, Enjyoji K, Friess H, Robson SC (2011) Variable impact of CD39 in experimental murine colitis. Dig Dis Sci 56:1393–1403
Kurahashi M, Zheng H, Dwyer L, Ward SM, Don KS, Sanders KM (2011) A functional role for the ‘fibroblast-like cells’ in gastrointestinal smooth muscles. J Physiol 589:697–710
Kurashima Y, Amiya T, Nochi T, Fujisawa K, Haraguchi T, Iba H, Tsutsui H, Sato S, Nakajima S, Iijima H, Kubo M, Kunisawa J, Kiyono H (2012) Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors. Nat Commun 3:1034
Kusu T, Kayama H, Kinoshita M, Jeon SG, Ueda Y, Goto Y, Okumura R, Saiga H, Kurakawa T, Ikeda K, Maeda Y, Nishimura J, Arima Y, Atarashi K, Honda K, Murakami M, Kunisawa J, Kiyono H, Okumura M, Yamamoto M, Takeda K (2013) Ecto-nucleoside triphosphate diphosphohydrolase 7 controls Th17 cell responses through regulation of luminal ATP in the small intestine. J Immunol 190:774–783
Langley JN (1898) On inhibitory fibres in the vagus to the end of the oesophagus and stomach. J Physiol 23:407–414
Lee HK, Ro S, Keef KD, Kim YH, Kim HW, Horowitz B, Sanders KM (2005) Differential expression of P2X-purinoceptor subtypes in circular and longitudinal muscle of canine colon. Neurogastroenterol Motil 17:575–584
LePard KJ, Messori E, Galligan JJ (1997) Purinergic fast excitatory postsynaptic potentials in myenteric neurons of guinea pig: distribution and pharmacology. Gastroenterology 113:1522–1534
Liñán-Rico A, Wunderlich JE, Grants IS, Frankel WL, Xue J, Williams KC, Harzman AE, Enneking JT, Cooke HJ, Christofi FL (2013) Purinergic autocrine regulation of mechanosensitivity and serotonin release in a human EC model: ATP-gated P2X3 channels in EC are downregulated in ulcerative colitis. Inflamm Bowel Dis 19:2366–2379
Lomax AE, O’Reilly M, Neshat S, Vanner SJ (2007) Sympathetic vasoconstrictor regulation of mouse colonic submucosal arterioles is altered in experimental colitis. J Physiol 583:719–730
Mabley J, Soriano F, Pacher P, Hasko G, Marton A, Wallace R, Salzman A, Szabo C (2003) The adenosine A3 receptor agonist, N6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide, is protective in two murine models of colitis. Eur J Pharmacol 466:323–329
Maor I, Rainis T, Lanir A, Lavy A (2011) Adenosine deaminase activity in patients with Crohn’s disease: distinction between active and nonactive disease. Eur J Gastroenterol Hepatol 23:598–602
Martinson J (1965) Studies on the efferent vagal control of the stomach. Acta Physiol Scand Suppl 255:1–24
Martinson J, Muren A (1963) Excitatory and inhibitory effects of vagus stimulation on gastric motility in the cat. Acta Physiol Scand 57:309–316
McSwiney BA, Robson JH (1929) The response of smooth muscle to stimulation of the vagus nerve. J Physiol 68:124–131
Michael S, Warstat C, Michel F, Yan L, Müller CE, Nieber K (2010) Adenosine A2A agonist and A2B antagonist mediate an inhibition of inflammation-induced contractile disturbance of a rat gastrointestinal preparation. Purinergic Signal 6:117–124
Mihara S, Katayama Y, Nishi S (1985) Slow postsynaptic potentials in neurones of the submucous plexus of guinea pig caecum and their mimickry by noradrenaline and various peptides. Neuroscience 16:1057–1066
Misawa R, Girotti PA, Mizuno MS, Liberti EA, Furness JB, Castelucci P (2010) Effects of protein deprivation and re-feeding on P2X2 receptors in enteric neurons. World J Gastroenterol 16:3651–3663
Monro RL, Bertrand PP, Bornstein JC (2004) ATP participates in three excitatory postsynaptic potentials in the submucous plexus of the guinea pig ileum. J Physiol 556:571–584
Moody CJ, Burnstock G (1982) Evidence for the presence of P1-purinoceptors on cholinergic nerve terminals in the guinea-pig ileum. Eur J Pharmacol 77:1–9
Naganuma M, Wiznerowicz EB, Lappas CM, Linden J, Worthington MT, Ernst PB (2006) Cutting edge: critical role for A2A adenosine receptors in the T cell-mediated regulation of colitis. J Immunol 177:2765–2769
Neshat S, DeVries M, Barajas-Espinosa AR, Skeith L, Chisholm SP, Lomax AE (2009) Loss of purinergic vascular regulation in the colon during colitis is associated with upregulation of CD39. Am J Physiol Gastrointest Liver Physiol 296:G399–G405
North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82:1013–1067
Odashima M, Bamias G, Rivera-Nieves J, Linden J, Nast CC, Moskaluk CA, Marini M, Sugawara K, Kozaiwa K, Otaka M, Watanabe S, Cominelli F (2005) Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease. Gastroenterology 129:26–33
Ohta T, Kubota A, Murakami M, Otsuguro K, Ito S (2005) P2X2 receptors are essential for [Ca2+]i increases in response to ATP in cultured rat myenteric neurons. Am J Physiol Gastrointest Liver Physiol 289:G935–G948
Olsson RA, Pearson JD (1990) Cardiovascular purinoceptors. Physiol Rev 70:761–845
Pacaud P, Feolde E, Frelin C, Loirand G (1996) Characterization of the P2Y-purinoceptor involved in the ATP-induced rise in cytosolic Ca2+ concentration in rat ileal myocytes. Br J Pharmacol 118:2213–2219
Page AJ, O’Donnell TA, Blackshaw LA (2000) P2X purinoceptor-induced sensitization of ferret vagal mechanoreceptors in oesophageal inflammation. J Physiol (Lond) 523:403–411
Paton WD (1958) Central and synaptic transmission in the nervous system; pharmacological aspects. Annu Rev Physiol 20:431–470
Paton WD, Vane JR (1963) Analysis of the responses of the isolated stomach to electrical stimulation and to drugs. J Physiol 165:10–46
Poole DP, Castelucci P, Robbins HL, Chiocchetti R, Furness JB (2002) The distribution of P2X3 purine receptor subunits in the guinea pig enteric nervous system. Auton Neurosci 101:39–47
Rahimian R, Fakhfouri G, Daneshmand A, Mohammadi H, Bahremand A, Rasouli MR, Mousavizadeh K, Dehpour AR (2010) Adenosine A2A receptors and uric acid mediate protective effects of inosine against TNBS-induced colitis in rats. Eur J Pharmacol 649:376–381
Ralevic V, Burnstock G (1998) Receptors for purines and pyrimidines. Pharmacol Rev 50:413–492
Ren J, Bertrand PP (2008) Purinergic receptors and synaptic transmission in enteric neurons. Purinergic Signal 4:255–266
Ren J, Galligan JJ (2005) Dynamics of fast synaptic excitation during trains of stimulation in myenteric neurons of guinea-pig ileum. Auton Neurosci 117:67–78
Ren J, Galligan JJ (2007) A novel calcium-sensitive potassium conductance is coupled to P2X3 subunit containing receptors in myenteric neurons of guinea pig ileum. Neurogastroenterol Motil 19:912–922
Ren J, Bian X, DeVries M, Schnegelsberg B, Cockayne DA, Ford AP, Galligan JJ (2003) P2X2 subunits contribute to fast synaptic excitation in myenteric neurons of the mouse small intestine. J Physiol 552:809–821
Ren T, Grants I, Alhaj M, McKiernan M, Jacobson M, Hassanain HH, Frankel W, Wunderlich J, Christofi FL (2011) Impact of disrupting adenosine A3 receptors (A3 -/- AR) on colonic motility or progression of colitis in the mouse. Inflamm Bowel Dis 17:1698–1713
Roberts JA, Durnin L, Sharkey KA, Mutafova-Yambolieva VN, Mawe GM (2013) Oxidative stress disrupts purinergic neuromuscular transmission in the inflamed colon. J Physiol 591:3725–3737
Rong W, Keating C, Sun B, Dong L, Grundy D (2009) Purinergic contribution to small intestinal afferent hypersensitivity in a murine model of postinfectious bowel disease. Neurogastroenterol Motil 21:665–671, e32
Ruan H-Z, Burnstock G (2005) The distribution of P2X5 purinergic receptors in the enteric nervous system. Cell Tissue Res 319:191–200
Rybaczyk L, Rozmiarek A, Circle K, Grants I, Needleman B, Wunderlich JE, Huang K, Christofi FL (2009) New bioinformatics approach to analyze gene expressions and signaling pathways reveals unique purine gene dysregulation profiles that distinguish between CD and UC. Inflamm Bowel Dis 15:971–984
Sakai K, Akima M, Matsushita H (1979) Analysis of the contractile responses of the ileal segment of the isolated blood-perfused small intestine of rats to adenosine triphosphate and related compounds. Eur J Pharmacol 58:157–162
Sarosi GA, Barnhart DC, Turner DJ, Mulholland MW (1998) Capacitative Ca2+ entry in enteric glia induced by thapsigargin and extracellular ATP. Am J Physiol 275:G550–G555
Siegmund B, Rieder F, Albrich S, Wolf K, Bidlingmaier C, Firestein GS, Boyle D, Lehr HA, Loher F, Hartmann G, Endres S, Eigler A (2001) Adenosine kinase inhibitor GP515 improves experimental colitis in mice. J Pharmacol Exp Ther 296:99–105
Sneddon JD, Smythe A, Satchell D, Burnstock G (1973) An investigation of the identity of the transmitter substance released by non-adrenergic, non-cholinergic excitatory nerves supplying the small intestine of some lower vertebrates. Comp Gen Pharmacol 4:53–60
Souza CO, Santoro GF, Figliuolo VR, Nanini HF, de Souza HS, Castelo-Branco MT, Abalo AA, Paiva MM, Coutinho CM, Coutinho-Silva R (2012) Extracellular ATP induces cell death in human intestinal epithelial cells. Biochim Biophys Acta 1820:1867–1878
Spencer NJ, Walsh M, Smith TK (2000) Purinergic and cholinergic neuro-neuronal transmission underlying reflexes activated by mucosal stimulation in the isolated guinea-pig ileum. J Physiol 522:321–331
Storr M, Franck H, Saur D, Schusdziarra V, Allescher HD (2000) Mechanisms of α, β-methylene ATPS-induced inhibition in rat ileal smooth muscle: involvement of intracellular Ca2+ stores in purinergic inhibition. Clin Exp Pharmacol Physiol 27:771–779
Strong DS, Cornbrooks CF, Roberts JA, Hoffman JM, Sharkey KA, Mawe GM (2010) Purinergic neuromuscular transmission is selectively attenuated in ulcerated regions of inflamed guinea pig distal colon. J Physiol 588:847–859
Su C, Bevan JA, Burnstock G (1971) [3H]adenosine triphosphate: release during stimulation of enteric nerves. Science 173:337–339
Tamada H, Hashitani H (2014) Calcium responses in subserosal interstitial cells of the guinea-pig proximal colon. Neurogastroenterol Motil 26:115–123
Thornton PD, Gwynne RM, McMillan DJ, Bornstein JC (2013) Transmission to interneurons is via slow excitatory synaptic potentials mediated by P2Y1 receptors during descending inhibition in guinea-pig ileum. PLoS One 8, e40840
Valdez-Morales E, Guerrero-Alba R, Liñan-Rico A, Espinosa-Luna R, Zarazua-Guzman S, Miranda-Morales M, Montaño LM, Barajas-López C (2011) P2X7 receptors contribute to the currents induced by ATP in guinea pig intestinal myenteric neurons. Eur J Pharmacol 668:366–372
Van Nassauw L, Brouns I, Adriaensen D, Burnstock G, Timmermans J-P (2002) Neurochemical identification of enteric neurons expressing P2X3 receptors in the guinea-pig ileum. Histochem Cell Biol 118:193–203
Van Nassauw L, Van Crombruggen K, De Jonge F, Burnstock G, Lefebvre RA, Timmermans J-P (2005) Distribution of P2Y receptor subtypes in the rat distal colon. Neurogastroenterol Motil 17:1
Van Nassauw L, Costagliola A, Van Op den bosch J, Cecio A, Vanderwinden J-M, Burnstock G, Timmermans J-P (2006) Region-specific distribution of the P2Y4 receptor in enteric glial cells and interstitial cells of Cajal within the guinea-pig gastrointestinal tract. Auton Neurosci 126–127:299–306
Vanderwinden JM, Timmermans JP, Schiffmann SN (2003) Glial cells, but not interstitial cells, express P2X7, an ionotropic purinergic receptor, in rat gastrointestinal musculature. Cell Tissue Res 312:149–154
Vial C, Evans RJ (2001) Smooth muscles does not have a common P2x receptor phenotype: expression, ontogeny and function of P2x1 receptors in mouse ileum, bladder and reproductive systems. Auton Neurosci 92:56–64
Wang GD, Wang XY, Hu HZ, Liu S, Gao N, Fang X, **a Y, Wood JD (2007) Inhibitory neuromuscular transmission mediated by the P2Y1 purinergic receptor in guinea pig small intestine. Am J Physiol Gastrointest Liver Physiol 292:G1483–G1489
Wood JD (2006) The enteric purinergic P2Y1 receptor. Curr Opin Pharmacol 6:564–570
Wunderlich JE, Needleman BJ, Chen Z, Yu JG, Wang Y, Grants I, Mikami DJ, Melvin WS, Cooke HJ, Christofi FL (2008) Dual purinergic synaptic transmission in the human enteric nervous system. Am J Physiol Gastrointest Liver Physiol 294:G554–G566
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
Wynn G, Rong W, **ang Z, Burnstock G (2003) Purinergic mechanisms contribute to mechanosensory transduction in the rat colorectum. Gastroenterology 125:1398–1409
Wynn G, Bei M, Ruan H-Z, Burnstock G (2004) Purinergic component of mechanosensory transduction is increased in a rat model of colitis. Am J Physiol Gastrointest Liver Physiol 287:G647–G657
**ang Z, Burnstock G (2004a) Development of nerves expressing P2X3 receptors in the myenteric plexus of rat stomach. Histochem Cell Biol 122:111–119
**ang Z, Burnstock G (2004b) P2X2 and P2X3 purinoceptors in the rat enteric nervous system. Histochem Cell Biol 121:169–179
**ang Z, Burnstock G (2005) Distribution of P2Y2 receptors in the guinea pig enteric nervous system and its coexistence with P2X2 and P2X3 receptors, neuropeptide Y, nitric oxide synthase and calretinin. Histochem Cell Biol 124:379–390
**ang Z, Burnstock G (2006) Distribution of P2Y6 and P2Y12 receptor: their colocalization with calbindin, calretinin and nitric oxide synthase in the guinea pig enteric nervous system. Histochem Cell Biol 125:327–336
Xu GY, Shenoy M, Winston JH, Mittal S, Pasricha PJ (2008) P2X receptor-mediated visceral hyperalgesia in a rat model of chronic visceral hypersensitivity. Gut 57:1230–1237
Ye JH, Rajendran VM (2009) Adenosine: an immune modulator of inflammatory bowel diseases. World J Gastroenterol 15:4491–4498
Yiangou Y, Facer P, Baecker PA, Ford AP, Knowles CH, Chan CL, Williams NS, Anand P (2001) ATP-gated ion channel P2X3 is increased in human inflammatory bowel disease. Neurogastroenterol Motil 13:365–369
Yu Q, Sun J, Guo W, Fu J, Xu X, Burnstock G, He C, **ang Z (2010) Expression of P2X6 receptors in the enteric nervous system of the rat gastrointestinal tract. Histochem Cell Biol 133:177–188
Zagorodnyuk V, Maggi CA (1998) Pharmacological evidence for the existence of multiple P2 receptors in the circular muscle of guinea-pig colon. Br J Pharmacol 123:122–128
Zhou X, Galligan JJ (1996) P2X purinoceptors in cultured myenteric neurons of guinea-pig small intestine. J Physiol 496:719–729
Zhou X, Galligan JJ (1998) Non-additive interaction between nicotinic cholinergic and P2X purine receptors in guinea-pig enteric neurons in culture. J Physiol 513:685–697
Zimmermann H (1994) Signalling via ATP in the nervous system. Trends Neurosci 17:420–426
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Burnstock, G. (2016). Purinergic Signalling in the Gut. In: Brierley, S., Costa, M. (eds) The Enteric Nervous System. Advances in Experimental Medicine and Biology(), vol 891. Springer, Cham. https://doi.org/10.1007/978-3-319-27592-5_10
Download citation
DOI: https://doi.org/10.1007/978-3-319-27592-5_10
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-27590-1
Online ISBN: 978-3-319-27592-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)