title: P2Y2 nucleotide receptor-mediated responses in brain cells.
abstract: Acute inflammation is important for tissue repair; however, chronic inflammation contributes to neurodegeneration in Alzheimer's disease (AD) and occurs when glial cells undergo prolonged activation. In the brain, stress or damage causes the release of nucleotides and activation of the G(q) protein-coupled P2Y(2) nucleotide receptor subtype (P2Y(2)R) leading to pro-inflammatory responses that can protect neurons from injury, including the stimulation and recruitment of glial cells. P2Y(2)R activation induces the phosphorylation of the epidermal growth factor receptor (EGFR), a response dependent upon the presence of a SH3 binding domain in the intracellular C terminus of the P2Y(2)R that promotes Src binding and transactivation of EGFR, a pathway that regulates the proliferation of cortical astrocytes. Other studies indicate that P2Y(2)R activation increases astrocyte migration. P2Y(2)R activation by UTP increases the expression in astrocytes of alpha(V)beta(3/5) integrins that bind directly to the P2Y(2)R via an Arg-Gly-Asp (RGD) motif in the first extracellular loop of the P2Y(2)R, an interaction required for G(o) and G(12) protein-dependent astrocyte migration. In rat primary cortical neurons (rPCNs) P2Y(2)R expression is increased by stimulation with interleukin-1beta (IL-1beta), a pro-inflammatory cytokine whose levels are elevated in AD, in part due to nucleotide-stimulated release from glial cells. Other results indicate that oligomeric beta-amyloid peptide (Abeta(1-42)), a contributor to AD, increases nucleotide release from astrocytes, which would serve to activate upregulated P2Y(2)Rs in neurons. Data with rPCNs suggest that P2Y(2)R upregulation by IL-1beta and subsequent activation by UTP are neuroprotective, since this increases the non-amyloidogenic cleavage of amyloid precursor protein. Furthermore, activation of IL-1beta-upregulated P2Y(2)Rs in rPCNs increases the phosphorylation of cofilin, a cytoskeletal protein that stabilizes neurite outgrowths. Thus, activation of pro-inflammatory P2Y(2)Rs in glial cells can promote neuroprotective responses, suggesting that P2Y(2)Rs represent a novel pharmacological target in neurodegenerative and other pro-inflammatory diseases.
authors.affiliation: Department of Biochemistry, Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA. troy.peterson1@gmail.com
authors.forename: Troy S
authors.initials: TS
authors.lastname: Peterson
authors.forename: Jean M
authors.initials: JM
authors.lastname: Camden
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Wang
authors.forename: Cheikh I
authors.initials: CI
authors.lastname: Seye
authors.forename: W G
authors.initials: WG
authors.lastname: Wood
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Sun
authors.forename: Laurie
authors.initials: L
authors.lastname: Erb
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Petris
authors.forename: Gary A
authors.initials: GA
authors.lastname: Weisman
mesh_terms: D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology* / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D055806:Microvessels / Q000378:metabolism; D008969:Molecular Sequence Data; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D017433:Protein Structure, Secondary; D018048:Receptors, Purinergic P2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D058473:Receptors, Purinergic P2Y2; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016564:Amyloid beta-Protein Precursor; C546387:P2ry2 protein, rat; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2
references.citation: Biochem J. 1998 Dec 15;336 ( Pt 3):513-23
references.pmid: 9841859
references.citation: J Neurosci. 2008 Nov 12;28(46):11760-7
references.pmid: 19005037
references.citation: J Immunol. 2009 Oct 1;183(7):4521-9
references.pmid: 19734210
references.citation: Br J Pharmacol. 1970 Dec;40(4):668-88
references.pmid: 4322041
references.citation: Brain Res Mol Brain Res. 1997 Dec 15;52(2):201-12
references.pmid: 9495541
references.citation: Nature. 1997 Feb 20;385(6618):729-33
references.pmid: 9034190
references.citation: J Biol Chem. 1995 Mar 3;270(9):4916-22
references.pmid: 7876266
references.citation: Science. 1992 Jan 17;255(5042):325-7
references.pmid: 1549777
references.citation: Arch Biochem Biophys. 2002 Jan 1;397(1):131-6
references.pmid: 11747319
references.citation: Annu Rev Cell Biol. 1994;10:373-403
references.pmid: 7888181
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8083-7
references.pmid: 7644542
references.citation: J Comp Neurol. 1991 Jan 15;303(3):375-86
references.pmid: 2007655
references.citation: J Biol Chem. 1993 Nov 5;268(31):22959-62
references.pmid: 8226807
references.citation: J Biol Chem. 1998 Sep 4;273(36):23110-7
references.pmid: 9722539
references.citation: Science. 2003 Oct 31;302(5646):834-8
references.pmid: 14593170
references.citation: Brain Pathol. 2004 Oct;14(4):426-32
references.pmid: 15605990
references.citation: J Physiol. 1995 Feb 15;483 ( Pt 1):41-57
references.pmid: 7776240
references.citation: Neuroscience. 2006 Oct 13;142(2):411-23
references.pmid: 16905269
references.citation: J Neurochem. 2007 Dec;103(5):1785-800
references.pmid: 17868308
references.citation: Biochem J. 1996 Mar 1;314 ( Pt 2):555-61
references.pmid: 8670070
references.citation: Glia. 1999 Jan;25(1):93-8
references.pmid: 9888301
references.citation: Glia. 1999 Dec;28(3):190-200
references.pmid: 10559778
references.citation: J Biol Chem. 2004 Nov 26;279(48):50310-20
references.pmid: 15371443
references.citation: Mol Aspects Med. 2003 Aug-Oct;24(4-5):305-13
references.pmid: 12893008
references.citation: Biochim Biophys Acta. 1999 Jan 12;1416(1-2):271-84
references.pmid: 9889382
references.citation: J Neurochem. 2000 May;74(5):1951-60
references.pmid: 10800938
references.citation: EMBO J. 2006 Feb 22;25(4):752-62
references.pmid: 16467848
references.citation: Adv Exp Med Biol. 1998;431:417-24
references.pmid: 9598102
references.citation: Biochim Biophys Acta. 1992 Feb 19;1134(1):61-72
references.pmid: 1311959
references.citation: Br J Anaesth. 2000 Apr;84(4):476-88
references.pmid: 10823099
references.citation: J Biol Chem. 1998 Jan 30;273(5):2653-60
references.pmid: 9446569
references.citation: J Biol Chem. 2005 Nov 25;280(47):39050-7
references.pmid: 16186116
references.citation: J Neurosci Res. 2001 Jan 15;63(2):109-15
references.pmid: 11169620
references.citation: Eur J Neurosci. 2003 Jun;17(11):2267-76
references.pmid: 12814360
references.citation: J Neurochem. 1997 Aug;69(2):704-12
references.pmid: 9231730
references.citation: Mol Immunol. 2008 Jan;45(1):65-75
references.pmid: 17599409
references.citation: J Neurotrauma. 2009 May;26(5):789-97
references.pmid: 19331521
references.citation: J Nutr Biochem. 2002 Aug;13(8):444
references.pmid: 12165357
references.citation: Mol Neurobiol. 2005;31(1-3):169-83
references.pmid: 15953819
references.citation: J Neurochem. 1995 Oct;65(4):1431-44
references.pmid: 7561836
references.citation: Eur Respir J. 1996 Mar;9(3):542-8
references.pmid: 8730017
references.citation: Br J Pharmacol. 1995 Dec;116(7):2909-18
references.pmid: 8680724
references.citation: J Neurosci. 2001 Mar 15;21(6):1975-82
references.pmid: 11245682
references.citation: Brain Res. 1998 Nov 2;809(2):297-301
references.pmid: 9853123
references.citation: Neuroscience. 1993 May;54(1):15-36
references.pmid: 8515840
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8999-9004
references.pmid: 12861073
references.citation: Cell. 1989 Apr 7;57(1):115-26
references.pmid: 2649245
references.citation: Neurochem Res. 1992 Sep;17(9):877-85
references.pmid: 1407275
references.citation: Neuron. 1993 Feb;10(2):243-54
references.pmid: 8094963
references.citation: Brain Res. 2004 Mar 12;1000(1-2):32-9
references.pmid: 15053949
references.citation: J Neurovirol. 2002 Dec;8(6):539-50
references.pmid: 12476348
references.citation: Curr Opin Neurobiol. 1996 Aug;6(4):526-32
references.pmid: 8794102
references.citation: Lancet Neurol. 2004 Apr;3(4):219-26
references.pmid: 15039034
references.citation: J Cell Biol. 2009 Jul 13;186(1):85-97
references.pmid: 19596849
references.citation: Science. 1992 Oct 9;258(5080):304-7
references.pmid: 1411529
references.citation: J Biol Chem. 2004 Feb 27;279(9):8212-8
references.pmid: 14670955
references.citation: Arzneimittelforschung. 1995 Mar;45(3A):435-8
references.pmid: 7763340
references.citation: Exp Neurol. 1994 Sep;129(1):112-9
references.pmid: 7925833
references.citation: Arch Oral Biol. 2005 Jun;50(6):533-40
references.pmid: 15848146
references.citation: FEBS Lett. 1989 Apr 24;247(2):386-90
references.pmid: 2653864
references.citation: Neurosci Lett. 1991 Jul 8;128(1):126-8
references.pmid: 1922940
references.citation: Circ Res. 2001 Oct 26;89(9):772-8
references.pmid: 11679406
references.citation: Am J Physiol. 1996 May;270(5 Pt 1):L695-703
references.pmid: 8967502
references.citation: J Neural Transm Suppl. 1994;44:21-7
references.pmid: 7897393
references.citation: J Neurosci. 2007 Mar 14;27(11):2866-75
references.pmid: 17360908
references.citation: J Cell Biol. 2004 Dec 6;167(5):961-72
references.pmid: 15569714
references.citation: Physiol Rev. 2001 Apr;81(2):741-66
references.pmid: 11274343
references.citation: J Biol Chem. 1994 Sep 9;269(36):22623-7
references.pmid: 8077213
references.citation: Science. 2006 Dec 15;314(5806):1792-5
references.pmid: 17170310
references.citation: J Biomed Biotechnol. 2002;2(3):120-123
references.pmid: 12488575
references.citation: Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9195-8
references.pmid: 8415676
references.citation: J Immunol. 2005 Jun 1;174(11):7268-77
references.pmid: 15905573
references.citation: J Biol Chem. 1996 Jan 5;271(1):337-42
references.pmid: 8550583
references.citation: Prog Brain Res. 1999;120:33-43
references.pmid: 10550986
references.citation: Cardiovasc Res. 1992 Jan;26(1):40-7
references.pmid: 1325292
references.citation: Trends Neurosci. 1997 Dec;20(12):570-7
references.pmid: 9416670
references.citation: Nihon Yakurigaku Zasshi. 2000 Apr;115(4):185-92
references.pmid: 10876802
references.citation: Brain Res. 1995 Apr 17;677(1):167-70
references.pmid: 7606463
references.citation: Int J Immunopathol Pharmacol. 2006 Apr-Jun;19(2):293-308
references.pmid: 16831297
references.citation: Physiol Rev. 1997 Oct;77(4):1081-132
references.pmid: 9354812
references.citation: Neurobiol Aging. 2005 Mar;26(3):349-54
references.pmid: 15639313
references.citation: J Neurosci Res. 2002 Nov 1;70(3):462-73
references.pmid: 12391607
references.citation: Pharmacol Ther. 2006 Mar;109(3):297-324
references.pmid: 16102837
references.citation: Circulation. 2001 Dec 18;104(25):3109-15
references.pmid: 11748109
references.citation: J Biol Chem. 1990 Mar 15;265(8):4492-7
references.pmid: 1968460
references.citation: Circ Res. 2002 Apr 5;90(6):678-81
references.pmid: 11934835
references.citation: Neurochem Res. 2001 Sep;26(8-9):959-69
references.pmid: 11699948
references.citation: Int J Dev Neurosci. 2001 Jul;19(4):395-414
references.pmid: 11378300
references.citation: Neurotoxicology. 1992 Spring;13(1):113-22
references.pmid: 1508411
references.citation: Mol Pharmacol. 1995 Jan;47(1):104-14
references.pmid: 7838119
references.citation: Ann N Y Acad Sci. 1993 Sep 24;695:122-7
references.pmid: 8239269
references.citation: Nature. 1992 Jun 11;357(6378):500-3
references.pmid: 1608449
references.citation: J Neurosci. 1999 Feb 1;19(3):940-7
references.pmid: 9920657
references.citation: J Cell Sci. 2009 Jul 15;122(Pt 14):2524-33
references.pmid: 19549686
references.citation: Pharmacol Rev. 1972 Sep;24(3):509-81
references.pmid: 4404211
references.citation: Nat Cell Biol. 2004 Nov;6(11):1054-61
references.pmid: 15516999
references.citation: Biochem Biophys Res Commun. 1999 May 19;258(3):648-52
references.pmid: 10329439
references.citation: Brain Res. 1998 Mar 2;785(2):195-206
references.pmid: 9518610
references.citation: J Cell Sci. 2007 May 1;120(Pt 9):1654-62
references.pmid: 17452627
references.citation: Am J Physiol Cell Physiol. 2001 Aug;281(2):C524-31
references.pmid: 11443051
references.citation: Science. 1996 Aug 30;273(5279):1227-31
references.pmid: 8703057
references.citation: J Neurochem. 1994 Aug;63(2):781-4
references.pmid: 8035204
references.citation: J Neurosci. 2003 Aug 20;23(20):7504-9
references.pmid: 12930788
references.citation: Glia. 2004 Jan 15;45(2):170-9
references.pmid: 14730710
references.citation: Free Radic Biol Med. 2002 Sep 1;33(5):620-6
references.pmid: 12208348
references.citation: J Biol Chem. 1996 Aug 23;271(34):20631-5
references.pmid: 8702810
references.citation: Free Radic Res. 2002 Dec;36(12):1307-13
references.pmid: 12607822
references.citation: Biochemistry. 2000 Jun 13;39(23):6951-9
references.pmid: 10841777
references.citation: J Neurochem. 2009 Jun;109(5):1300-10
references.pmid: 19317852
references.citation: J Biol Chem. 2005 May 13;280(19):18696-702
references.pmid: 15778502
references.citation: J Neurochem. 1999 Feb;72(2):443-60
references.pmid: 9930716
references.citation: Neurobiol Aging. 2004 Apr;25(4):431-9
references.pmid: 15013563
references.citation: Circ Res. 2008 Mar 14;102(5):581-8
references.pmid: 18202316
references.citation: Circulation. 2002 Nov 19;106(21):2720-6
references.pmid: 12438299
references.citation: Proc Natl Acad Sci U S A. 1997 Feb 4;94(3):831-6
references.pmid: 9023342
references.citation: Neurosci Biobehav Rev. 1999 May;23(5):615-33
references.pmid: 10392655
references.citation: Curr Opin Lipidol. 2002 Jun;13(3):289-94
references.pmid: 12045399
references.citation: J Neurosurg. 1997 Sep;87(3):420-30
references.pmid: 9285609
references.citation: Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):2064-9
references.pmid: 10978250
references.citation: J Auton Pharmacol. 1996 Dec;16(6):397-400
references.pmid: 9131425
references.citation: J Biol Chem. 2009 Oct 16;284(42):28554-62
references.pmid: 19696021
references.citation: J Biol Chem. 1996 Feb 23;271(8):4188-94
references.pmid: 8626761
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19138-43
references.pmid: 16365320
references.citation: J Biol Chem. 2003 Jul 4;278(27):24960-5
references.pmid: 12714597
references.citation: Trends Neurosci. 1996 Jan;19(1):13-8
references.pmid: 8787135
references.citation: Neurobiol Aging. 2004 May-Jun;25(5):663-74
references.pmid: 15172746