title: The nNOS-p38MAPK pathway is mediated by NOS1AP during neuronal death.
abstract: Neuronal nitric oxide synthase (nNOS) and p38MAPK are strongly implicated in excitotoxicity, a mechanism common to many neurodegenerative conditions, but the intermediary mechanism is unclear. NOS1AP is encoded by a gene recently associated with sudden cardiac death, diabetes-associated complications, and schizophrenia (Arking et al., 2006; Becker et al., 2008; Brzustowicz, 2008; Lehtinen et al., 2008). Here we find it interacts with p38MAPK-activating kinase MKK3. Excitotoxic stimulus induces recruitment of NOS1AP to nNOS in rat cortical neuron culture. Excitotoxic activation of p38MAPK and subsequent neuronal death are reduced by competing with the nNOS:NOS1AP interaction and by knockdown with NOS1AP-targeting siRNAs. We designed a cell-permeable peptide that competes for the unique PDZ domain of nNOS that interacts with NOS1AP. This peptide inhibits NMDA-induced recruitment of NOS1AP to nNOS and in vivo in rat, doubles surviving tissue in a severe model of neonatal hypoxia-ischemia, a major cause of neonatal death and pediatric disability. The highly unusual sequence specificity of the nNOS:NOS1AP interaction and involvement in excitotoxic signaling may provide future opportunities for generation of neuroprotectants with high specificity.
authors: Molecular Signalling Laboratory, Department of Neurobiology, A.I. Virtanen Institute, University of Eastern Finland, FI-70211 Kuopio, Finland.
authors: Li-Li
authors: LL
authors: Li
authors: Vanessa
authors: V
authors: Ginet
authors: Xiaonan
authors: X
authors: Liu
authors: Olga
authors: O
authors: Vergun
authors: Minna
authors: M
authors: Tuittila
authors: Marc
authors: M
authors: Mathieu
authors: Christophe
authors: C
authors: Bonny
authors: Julien
authors: J
authors: Puyal
authors: Anita C
authors: AC
authors: Truttmann
authors: Michael J
authors: MJ
authors: Courtney
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D011487:Protein Conformation; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D047908:Intracellular Signaling Peptides and Proteins; C488082:NOS1AP protein, rat; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D010455:Peptides; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D049452:Green Fluorescent Proteins; D016202:N-Methylaspartate; D007770:L-Lactate Dehydrogenase; D052248:Nitric Oxide Synthase Type I; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium
references: Nat Biotechnol. 1997 Apr;15(4):336-42
references: 9094134
references: J Neurosci. 2002 Oct 15;22(20):8961-70
references: 12388603
references: Nat Med. 2010 Dec;16(12):1439-43
references: 21102461
references: J Neurosci. 2008 Oct 15;28(42):10696-710
references: 18923045
references: J Biol Chem. 2005 May 20;280(20):19472-9
references: 15755732
references: J Neurosci. 2009 Jan 21;29(3):669-77
references: 19158293
references: Stroke. 1997 Jun;28(6):1283-8
references: 9183363
references: J Neurosci. 2007 Sep 12;27(37):9901-15
references: 17855605
references: J Biochem. 2003 Feb;133(2):181-7
references: 12761180
references: Neurobiol Dis. 1996 Feb;3(1):64-71
references: 9173913
references: J Biol Chem. 1999 Sep 24;274(39):27467-73
references: 10488080
references: J Neurochem. 2003 Jul;86(2):306-17
references: 12871572
references: J Neurosci. 2002 Jun 1;22(11):4335-45
references: 12040039
references: J Neurosci. 2005 Jul 6;25(27):6350-61
references: 16000625
references: Neuron. 1991 Oct;7(4):615-24
references: 1718335
references: J Neurochem. 2004 Feb;88(3):759-68
references: 14720225
references: J Neurosci. 1998 Mar 1;18(5):1725-34
references: 9464997
references: Curr Psychiatry Rep. 2008 Apr;10(2):158-63
references: 18474209
references: Br J Pharmacol. 2009 Sep;158(2):494-506
references: 19732061
references: Brain Res. 2000 Dec 29;887(2):316-22
references: 11134621
references: Nat Genet. 2006 Jun;38(6):644-51
references: 16648850
references: Stroke. 2002 Aug;33(8):2123-36
references: 12154275
references: Eur J Neurosci. 2004 Mar;19(5):1163-73
references: 15016075
references: Diabetes. 2008 Apr;57(4):1108-14
references: 18235038
references: Science. 1997 Aug 1;277(5326):693-6
references: 9235893
references: Nat Rev Neurosci. 2004 Oct;5(10):771-81
references: 15378037
references: Biochemistry. 2001 May 22;40(20):5921-30
references: 11352727
references: J Mol Biol. 2000 Oct 27;303(3):359-70
references: 11031113
references: Neuron. 2000 Oct;28(1):183-93
references: 11086993
references: Ann Neurol. 2009 Mar;65(3):337-47
references: 19334077
references: Trends Cell Biol. 2007 Jul;17(7):343-52
references: 17644382
references: Dev Neurobiol. 2007 Mar;67(4):422-37
references: 17443799
references: Eur J Neurosci. 1999 Mar;11(3):1073-84
references: 10103100
references: J Biol Chem. 2001 Apr 6;276(14):11382-6
references: 11152698
references: Neuron. 1998 Jan;20(1):115-24
references: 9459447
references: Stroke. 2003 May;34(5):1299-303
references: 12677017
references: Stroke. 2004 Jul;35(7):1738-43
references: 15178829
references: Nat Struct Biol. 1999 May;6(5):417-21
references: 10331866
references: J Neurochem. 2009 Feb;108(3):552-62
references: 19046406
references: Nat Neurosci. 2011 Mar;14(3):305-13
references: 21297631
references: Nat Neurosci. 2007 Apr;10(4):436-43
references: 17369826
references: FEBS Lett. 1997 Jun 2;409(1):53-6
references: 9199503
references: Angew Chem Int Ed Engl. 1999 Nov 2;38(21):3209-3212
references: 10556905
references: Trends Neurosci. 1997 Mar;20(3):132-9
references: 9061868
references: Science. 2002 Oct 25;298(5594):846-50
references: 12399596
references: Pediatr Res. 1994 Jan;35(1):10-4
references: 8134185
references: J Biol Chem. 2004 Oct 22;279(43):44955-65
references: 15310755
references: J Neurosci. 2005 Jul 13;25(28):6520-32
references: 16014713
references: Nat Med. 2003 Sep;9(9):1180-6
references: 12937412
references: Eur J Neurosci. 2011 May;33(9):1647-55
references: 21453290
references: Biochem J. 2001 Aug 1;357(Pt 3):593-615
references: 11463332
references: Ann Neurol. 1981 Feb;9(2):131-41
references: 7235629
references: J Biol Chem. 1997 Jul 25;272(30):18518-21
references: 9228012
references: Dev Neurosci. 2002;24(5):405-10
references: 12640179
references: Expert Opin Ther Targets. 2008 Jan;12(1):31-43
references: 18076368
references: Science. 1999 Apr 30;284(5415):812-5
references: 10221915
references: J Biol Chem. 2012 Jan 20;287(4):2364-77
references: 22123824
references: Lancet Neurol. 2012 Nov;11(11):942-50
references: 23051991
references: Brain Dev. 2001 Aug;23(5):349-54
references: 11504607
references: J Neurochem. 2006 Mar;96(6):1531-9
references: 16464237
references: Pharmacogenet Genomics. 2008 Jul;18(7):591-7
references: 18551039
references: J Neurosci. 1990 Dec;10(12):3873-9
references: 1980131
references: Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2151-5
references: 7510887
references: J Neurovirol. 2008 Oct;14(5):376-88
references: 19003592
references: J Cell Biol. 2005 Jan 3;168(1):117-26
references: 15631993
references: J Neurosci. 2001 Feb 15;21(4):1211-7
references: 11160391
references: Neuron. 2006 Oct 19;52(2):307-20
references: 17046693
references: J Biol Chem. 2004 Aug 20;279(34):35903-13
references: 15192112