Abstract
Extracellular adenosine 5′-triphosphate (ATP) is a key signaling molecule present in the central nervous system (CNS), and now is receiving greater attention due to its role as a messenger in the CNS during different physiological and pathological events. ATP is released into the extracellular space through vesicular exocytosis or from damaged and dying cells. Once in the extracellular environment, ATP binds to the specific receptors termed P2, which mediate ATP effects and are present broadly in both neurons and glial cells. There are P2X, the ligand-gated ionotropic receptors, possessing low affinity for ATP and responsible for fast excitatory neurotransmission, and P2Y, the metabotropic G-protein-coupled receptors, possessing high affinity for ATP. Since massive extracellular release of ATP often occurs after stress, brain ischemia and trauma, the extracellular ATP is considered relating to or involving in the pathological processes of many nervous system diseases. Conversely, the trophic functions have also been extensively described for the extracellular ATP. Therefore, extracellular ATP plays a very complex role in the CNS and its binding to P2 receptors can be related to toxic and/or beneficial effects. In this review, we described the extracellular ATP acting via P2 receptors as a potent therapeutic target for treatment of nervous system diseases.
Keywords: extracellular ATP, P2 receptors, nervous system diseases
ÕaÒa
在中枢神经系统中, 胞外ATP 是一种重要的信号转导分子, 目前, 它在中枢神经系统中的生理及病理作用已经得到了广泛的关注。 ATP可以通过囊泡胞吐形式被相关神经细胞释放到细胞外, 也可以因为细胞的损伤被直接释放出来。 在细胞外环境中, ATP 可以结合到它的特异性P2 受体上, 从而介导各种作用。 P2 受体有P2X 和P2Y 两种类型, 其中P2X 型受体是一类配体门控型的离子通道型受体, 这类受体对ATP的亲和力较低, 介导快速神经传递作用; P2Y 型受体是一类与代谢相关的G蛋白耦联受体, 对ATP的亲和力高。 由于大规模的ATP外释现象一般出现在各类应激、 脑缺血、 脑损伤之后, 因此细胞外ATP 被认为参与了神经系统疾病的病理过程。 但是, 大量报道也指出了细胞外ATP的营养功能。 因此, 可以认为细胞外ATP在中枢神经系统中扮演着非常复杂的角色, 结合特异性P2受体后, 可以引发有害性或有益性的结果。 本综述着重叙述了细胞外ATP作为神经系统疾病治疗靶点的潜能。
关键词: 细胞外ATP, P2 受体, 神经系统疾病
References
- [1].Khakh B.S., North R.A. P2X receptors as cell-surface ATP sensors in health and disease. Nature. 2006;442:527–532. doi: 10.1038/nature04886. [DOI] [PubMed] [Google Scholar]
- [2].Ralevic V., Burnstock G. Receptors for purines and pyrimidines. Pharmacol Rev. 1998;50:413–492. [PubMed] [Google Scholar]
- [3].Burnstock G. Purinergic nerves. Pharmacol Rev. 1972;24:509–581. [PubMed] [Google Scholar]
- [4].Franke H., Krugel U., Illes P. P2 receptors and neuronal injury. Pflugers Arch. 2006;452:622–644. doi: 10.1007/s00424-006-0071-8. [DOI] [PubMed] [Google Scholar]
- [5].Khakh B.S. Molecular physiology of P2X receptors and ATP signalling at synapses. Nat Rev Neurosci. 2001;2:165–174. doi: 10.1038/35058521. [DOI] [PubMed] [Google Scholar]
- [6].Khakh B.S., Bao X.R., Labarca C., Lester H.A. Neuronal P2X transmitter-gated cation channels change their ion selectivity in seconds. Nat Neurosci. 1999;2:322–330. doi: 10.1038/7233. [DOI] [PubMed] [Google Scholar]
- [7].Egan T.M., Samways D.S., Li Z. Biophysics of P2X receptors. Pflugers Arch. 2006;452:501–512. doi: 10.1007/s00424-006-0078-1. [DOI] [PubMed] [Google Scholar]
- [8].Norenberg W., Illes P. Neuronal P2X receptors: localisation and functional properties. Naunyn Schmiedebergs Arch Pharmacol. 2000;362:324–339. doi: 10.1007/s002100000311. [DOI] [PubMed] [Google Scholar]
- [9].Franke H., Illes P. Involvement of P2 receptors in the growth and survival of neurons in the CNS. Pharmacol Ther. 2006;109:297–324. doi: 10.1016/j.pharmthera.2005.06.002. [DOI] [PubMed] [Google Scholar]
- [10].Khakh B.S., Burnstock G., Kennedy C., King B.F., North R.A., Séguéla P., et al. International union of pharmacology. XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits. Pharmacol Rev. 2001;53:107–118. [PubMed] [Google Scholar]
- [11].Chen Z.P., Krull N., Xu S., Levy A., Lightman S.L. Molecular cloning and functional characterization of a rat pituitary G proteincoupled adenosine triphosphate (ATP) receptor. Endocrinology. 1996;137:1833–1840. doi: 10.1210/en.137.5.1833. [DOI] [PubMed] [Google Scholar]
- [12].Chang K., Hanaoka K., Kumada M., Takuwa Y. Molecular cloning and functional analysis of a novel P2 nucleotide receptor. J Biol Chem. 1995;270:26152–26158. doi: 10.1074/jbc.270.44.26152. [DOI] [PubMed] [Google Scholar]
- [13].Communi D., Govaerts C., Parmentier M., Boeynaems J.M. Cloning of a human purinergic P2Y receptor coupled to phospholipase C and adenylyl cyclase. J Biol Chem. 1997;272:31969–31973. doi: 10.1074/jbc.272.51.31969. [DOI] [PubMed] [Google Scholar]
- [14].Hollopeter G., Jantzen H.M., Vincent D., Li G., England L., Ramakrishnan V., et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature. 2001;409:202–207. doi: 10.1038/35051599. [DOI] [PubMed] [Google Scholar]
- [15].Communi D., Gonzalez N.S., Detheux M., Brezillon S., Lannoy V., Parmentier M., et al. Identification of a novel human ADP receptor coupled to Gi. J Biol Chem. 2001;276:41479–41485. doi: 10.1074/jbc.M105912200. [DOI] [PubMed] [Google Scholar]
- [16].Bergfeld G.R., Forrester T. Release of ATP from human erythrocytes in response to a brief period of hypoxia and hypercapnia. Cardiovasc Res. 1992;26:40–47. doi: 10.1093/cvr/26.1.40. [DOI] [PubMed] [Google Scholar]
- [17].Ellsworth M.L. The red blood cell as an oxygen sensor: what is the evidence? Acta Physiol Scand. 2000;168:551–559. doi: 10.1046/j.1365-201x.2000.00708.x. [DOI] [PubMed] [Google Scholar]
- [18].Ellsworth M.L., Forrester T., Ellis C.G., Dietrich H.H. The erythrocyte as a regulator of vascular tone. Am J Physiol. 1995;269:H2155–H2161. doi: 10.1152/ajpheart.1995.269.6.H2155. [DOI] [PubMed] [Google Scholar]
- [19].Sprague R.S., Ellsworth M.L., Stephenson A.H., Lonigro A.J. ATP: the red blood cell link to NO and local control of the pulmonary circulation. Am J Physiol. 1996;271:H2717–H2722. doi: 10.1152/ajpheart.1996.271.6.H2717. [DOI] [PubMed] [Google Scholar]
- [20].Sprague R.S., Ellsworth M.L., Stephenson A.H., Kleinhenz M.E., Lonigro A.J. Deformation-induced ATP release from red blood cells requires CFTR activity. Am J Physiol. 1998;275:H1726–H1732. doi: 10.1152/ajpheart.1998.275.5.H1726. [DOI] [PubMed] [Google Scholar]
- [21].Ollivier H., Pichavant-Rafini K., Puill-Stephan E., Calves P., Nonnotte L., Nonnotte G. Effects of hypo-osmotic stress on ATP release in isolated turbot (Scophthalmus maximus) hepatocytes. Biol Cell. 2006;98:427–437. doi: 10.1042/BC20050077. [DOI] [PubMed] [Google Scholar]
- [22].Abraham E.H., Prat A.G., Gerweck L., Seneveratne T., Arceci R.J., Kramer R., et al. The multidrug resistance (mdr1) gene product functions as an ATP channel. Proc Natl Acad Sci USA. 1993;90:312–316. doi: 10.1073/pnas.90.1.312. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [23].De Robertis E., Pellegrino De Iraldi A., Rodriguez G., Gomez C.J. On the isolation of nerve endings and synaptic vesicles. J Biophys Biochem Cytol. 1961;9:229–235. doi: 10.1083/jcb.9.1.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [24].Nagasawa J. Exocytosis: the common release mechanism of secretory granules in glandular cells, neurosecretory cells, neurons and paraneurons. Arch Histol Jpn. 1977;40(Suppl):31–47. doi: 10.1679/aohc1950.40.supplement_31. [DOI] [PubMed] [Google Scholar]
- [25].Johnson R.G., Jr. Proton pumps and chemiosmotic coupling as a generalized mechanism for neurotransmitter and hormone transport. Ann N Y Acad Sci. 1987;493:162–177. doi: 10.1111/j.1749-6632.1987.tb27198.x. [DOI] [PubMed] [Google Scholar]
- [26].Chaudry I.H. Does ATP cross the cell plasma membrane. Yale J Biol Med. 1982;55:1–10. [PMC free article] [PubMed] [Google Scholar]
- [27].Fredholm B.B., Hedqvist P. Release of 3H-purines from [3H]-adenine labelled rabbit kidney following sympathetic nerve stimulation, and its inhibition by alpha-adrenoceptor blockage. Br J Pharmacol. 1978;64:239–245. doi: 10.1111/j.1476-5381.1978.tb17295.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [28].Vizi E.S., Burnstock G. Origin of ATP release in the rat vas deferens: concomitant measurement of [3H]noradrenaline and [14C]ATP. Eur J Pharmacol. 1988;158:69–77. doi: 10.1016/0014-2999(88)90254-3. [DOI] [PubMed] [Google Scholar]
- [29].Vizi E.S., Sperlagh B., Baranyi M. Evidence that ATP released from the postsynaptic site by noradrenaline, is involved in mechanical responses of guinea-pig vas deferens: cascade transmission. Neuroscience. 1992;50:455–465. doi: 10.1016/0306-4522(92)90437-7. [DOI] [PubMed] [Google Scholar]
- [30].Lagercrantz H., Stajarne L. Evidence that most noradrenaline is stored without ATP in sympathetic large dense core nerve vesicles. Nature. 1974;249:843–845. doi: 10.1038/249843a0. [DOI] [PubMed] [Google Scholar]
- [31].Burnstock G. Noradrenaline and ATP: cotransmitters and neuromodulators. J Physiol Pharmacol. 1995;46:365–384. [PubMed] [Google Scholar]
- [32].Burnstock G. Purinergic cotransmission. Brain Res Bull. 1999;50:355–357. doi: 10.1016/S0361-9230(99)00103-3. [DOI] [PubMed] [Google Scholar]
- [33].Dowdall M.J., Boyne A.F., Whittaker V.P. Adenosine triphosphate. A constituent of cholinergic synaptic vesicles. Biochem J. 1974;140:1–12. doi: 10.1042/bj1400001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [34].Hammond J.R., MacDonald W.F., White T.D. Evoked secretion of [3H]noradrenaline and ATP from nerve varicosities isolated from the myenteric plexus of the guinea pig ileum. Can J Physiol Pharmacol. 1988;66:369–375. doi: 10.1139/y88-062. [DOI] [PubMed] [Google Scholar]
- [35].White T.D. Release of ATP from a synaptosomal preparation by elevated extracellular K+ and by veratridine. J Neurochem. 1978;30:329–336. doi: 10.1111/j.1471-4159.1978.tb06534.x. [DOI] [PubMed] [Google Scholar]
- [36].Kasakov L., Ellis J., Kirkpatrick K., Milner P., Burnstock G. Direct evidence for concomitant release of noradrenaline, adenosine 5′-triphosphate and neuropeptide Y from sympathetic nerve supplying the guinea-pig vas deferens. J Auton Nerv Syst. 1988;22:75–82. doi: 10.1016/0165-1838(88)90156-7. [DOI] [PubMed] [Google Scholar]
- [37].Santos P.F., Caramelo O.L., Carvalho A.P., Duarte C.B. Characterization of ATP release from cultures enriched in cholinergic amacrine-like neurons. J Neurobiol. 1999;41:340–348. doi: 10.1002/(SICI)1097-4695(19991115)41:3<340::AID-NEU3>3.0.CO;2-8. [DOI] [PubMed] [Google Scholar]
- [38].Rathbone M.P., Middlemiss P.J., Gysbers J.W., Andrew C., Herman M.A., Reed J.K., et al. Trophic effects of purines in neurons and glial cells. Prog Neurobiol. 1999;59:663–690. doi: 10.1016/S0301-0082(99)00017-9. [DOI] [PubMed] [Google Scholar]
- [39].Zhang M., Zhong H., Vollmer C., Nurse C.A. Co-release of ATP and ACh mediates hypoxic signalling at rat carotid body chemoreceptors. J Physiol. 2000;525(Pt1):143–158. doi: 10.1111/j.1469-7793.2000.t01-1-00143.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [40].Bobalova J., Mutafova-Yambolieva V.N. Presynaptic α2-adrenoceptor-mediated modulation of adenosine 5′-triphosphate and noradrenaline corelease: differences in canine mesenteric artery and vein. J Auton Pharmacol. 2001;21:47–55. doi: 10.1046/j.1365-2680.2001.00207.x. [DOI] [PubMed] [Google Scholar]
- [41].Jo Y.H., Schlichter R. Synaptic corelease of ATP and GABA in cultured spinal neurons. Nat Neurosci. 1999;2:241–245. doi: 10.1038/6344. [DOI] [PubMed] [Google Scholar]
- [42].Amadio S., D’Ambrosi N., Cavaliere F., Murra B., Sancesario G., Bernardi G., et al. P2 receptor modulation and cytotoxic function in cultured CNS neurons. Neuropharmacology. 2002;42:489–501. doi: 10.1016/S0028-3908(01)00197-6. [DOI] [PubMed] [Google Scholar]
- [43].Kharlamov A., Jones S.C., Kim D.K. Suramin reduces infarct volume in a model of focal brain ischemia in rats. Exp Brain Res. 2002;147:353–359. doi: 10.1007/s00221-002-1251-1. [DOI] [PubMed] [Google Scholar]
- [44].Volonte C., Amadio S., Cavaliere F., D’Ambrosi N., Vacca F., Bernardi G. Extracellular ATP and neurodegeneration. Curr Drug Targets CNS Neurol Disord. 2003;2:403–412. doi: 10.2174/1568007033482643. [DOI] [PubMed] [Google Scholar]
- [45].Wirkner K., Kofalvi A., Fischer W., Gunther A., Franke H., Groger-Arndt H., et al. Supersensitivity of P2X receptors in cerebrocortical cell cultures after in vitro ischemia. J Neurochem. 2005;95:1421–1437. doi: 10.1111/j.1471-4159.2005.03465.x. [DOI] [PubMed] [Google Scholar]
- [46].Le Feuvre R.A., Brough D., Touzani O., Rothwell N.J. Role of P2X7 receptors in ischemic and excitotoxic brain injury in vivo. J Cereb Blood Flow Metab. 2003;23:381–384. doi: 10.1097/00004647-200303000-00013. [DOI] [PubMed] [Google Scholar]
- [47].Volonte C., Ciotti M.T., D’Ambrosi N., Lockhart B., Spedding M. Neuroprotective effects of modulators of P2 receptors in primary culture of CNS neurones. Neuropharmacology. 1999;38:1335–1342. doi: 10.1016/S0028-3908(99)00034-9. [DOI] [PubMed] [Google Scholar]
- [48].Cavaliere F., D’Ambrosi N., Ciotti M.T., Mancino G., Sancesario G., Bernardi G., et al. Glucose deprivation and chemical hypoxia: neuroprotection by P2 receptor antagonists. Neurochem Int. 2001;38:189–197. doi: 10.1016/S0197-0186(00)00088-7. [DOI] [PubMed] [Google Scholar]
- [49].Runden-Pran E., Tanso R., Haug F.M., Ottersen O.P., Ring A. Neuroprotective effects of inhibiting N-methyl-D-aspartate receptors, P2X receptors and the mitogen-activated protein kinase cascade: a quantitative analysis in organotypical hippocampal slice cultures subjected to oxygen and glucose deprivation. Neuroscience. 2005;136:795–810. doi: 10.1016/j.neuroscience.2005.08.069. [DOI] [PubMed] [Google Scholar]
- [50].Franke H., Schepper C., Illes P., Krugel U. Involvement of P2X and P2Y receptors in microglial activation in vivo. Purinergic Signal. 2007;3:435–445. doi: 10.1007/s11302-007-9082-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [51].Kucher B.M., Neary J.T. Bi-functional effects of ATP/P2 receptor activation on tumor necrosis factor-α release in lipopolysaccharide-stimulated astrocytes. J Neurochem. 2005;92:525–535. doi: 10.1111/j.1471-4159.2004.02885.x. [DOI] [PubMed] [Google Scholar]
- [52].Fields R.D., Stevens B. ATP: an extracellular signaling molecule between neurons and glia. Trends Neurosci. 2000;23:625–633. doi: 10.1016/S0166-2236(00)01674-X. [DOI] [PubMed] [Google Scholar]
- [53].Gendron F.P., Chalimoniuk M., Strosznajder J., Shen S., Gonzalez F.A., Weisman G.A., et al. P2X7 nucleotide receptor activation enhances IFN γ-induced type II nitric oxide synthase activity in BV-2 microglial cells. J Neurochem. 2003;87:344–352. doi: 10.1046/j.1471-4159.2003.01995.x. [DOI] [PubMed] [Google Scholar]