title: Activation of EphA receptors mediates the recruitment of the adaptor protein Slap, contributing to the downregulation of N-methyl-D-aspartate receptors.
abstract: Regulation of the activity of N-methyl-d-aspartate receptors (NMDARs) at glutamatergic synapses is essential for certain forms of synaptic plasticity underlying learning and memory and is also associated with neurotoxicity and neurodegenerative diseases. In this report, we investigate the role of Src-like adaptor protein (Slap) in NMDA receptor signaling. We present data showing that in dissociated neuronal cultures, activation of ephrin (Eph) receptors by chimeric preclustered eph-Fc ligands leads to recruitment of Slap and NMDA receptors at the sites of Eph receptor activation. Interestingly, our data suggest that prolonged activation of EphA receptors is as efficient in recruiting Slap and NMDA receptors as prolonged activation of EphB receptors. Using established heterologous systems, we examined whether Slap is an integral part of NMDA receptor signaling. Our results showed that Slap does not alter baseline activity of NMDA receptors and does not affect Src-dependent potentiation of NMDA receptor currents in Xenopus oocytes. We also demonstrate that Slap reduces excitotoxic cell death triggered by activation of NMDARs in HEK293 cells. Finally, we present evidence showing reduced levels of NMDA receptors in the presence of Slap occurring in an activity-dependent manner, suggesting that Slap is part of a mechanism that homeostatically modulates the levels of NMDA receptors.
authors: Centre of Biomedical Sciences, School of Biological Sciences, Royal Holloway University London, Surrey, United Kingdom.
authors: Sophia
authors: S
authors: Semerdjieva
authors: Hayder H
authors: HH
authors: Abdul-Razak
authors: Sharifah S
authors: SS
authors: Salim
authors: Rafael J
authors: RJ
authors: Yáñez-Muñoz
authors: Philip E
authors: PE
authors: Chen
authors: Victor
authors: V
authors: Tarabykin
authors: Pavlos
authors: P
authors: Alifragis
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D036081:Receptors, Eph Family / Q000235:genetics* / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014982:Xenopus laevis / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016194:Receptors, N-Methyl-D-Aspartate; C490636:Sla protein, rat; D036081:Receptors, Eph Family; D016392:Proto-Oncogene Proteins pp60(c-src)
references: J Neurosci. 1997 Oct 1;17(19):7339-50
references: 9295380
references: Annu Rev Neurosci. 1998;21:309-45
references: 9530499
references: Neuron. 2005 Apr 21;46(2):205-17
references: 15848800
references: Cell. 2000 Dec 8;103(6):945-56
references: 11136979
references: J Neurochem. 1998 Oct;71(4):1471-81
references: 9751180
references: J Neurochem. 2006 Jul;98(1):1-10
references: 16805791
references: J Physiol Paris. 1994;88(3):181-92
references: 7530547
references: Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5600-5
references: 15809437
references: J Cell Biochem. 2010 May;110(1):201-9
references: 20225239
references: Brain Res Brain Res Rev. 2005 Sep;49(2):211-26
references: 16111551
references: Mol Cell Biol. 2000 May;20(10):3396-406
references: 10779329
references: Curr Opin Cell Biol. 2004 Oct;16(5):580-9
references: 15363810
references: Neuroscientist. 2004 Aug;10(4):304-14
references: 15271258
references: J Cell Biol. 2003 Dec 22;163(6):1313-26
references: 14691139
references: J Neurosci Methods. 2008 Jun 30;171(2):239-47
references: 18471889
references: Front Biosci. 2004 May 01;9:1365-73
references: 14977552
references: J Physiol. 2008 Jan 1;586(1):227-45
references: 17962328
references: Immunol Rev. 2009 Nov;232(1):218-28
references: 19909366
references: J Biomed Opt. 2011 Nov;16(11):117001
references: 22112133
references: J Biol Chem. 1995 Aug 18;270(33):19201-4
references: 7543898
references: Nature. 1994 May 19;369(6477):233-5
references: 7514272
references: Nat Neurosci. 2004 Jan;7(1):33-40
references: 14699416
references: Science. 2002 Jun 7;296(5574):1864-9
references: 12052960
references: Neuron. 2001 Dec 20;32(6):1041-56
references: 11754836
references: J Neurosci. 1999 Nov 1;19(21):9538-49
references: 10531456
references: Invest Ophthalmol Vis Sci. 2010 Feb;51(2):991-1001
references: 19815726
references: Prog Neurobiol. 2010 Aug;91(4):313-48
references: 20438797
references: PLoS One. 2010 Aug 31;5(8):e12486
references: 20824214
references: Pflugers Arch. 2010 Jul;460(2):525-42
references: 20229265
references: Nat Rev Neurosci. 2001 Mar;2(3):205-9
references: 11256081
references: Eur J Neurosci. 1997 Jan;9(1):177-88
references: 9042581
references: Mol Cell Neurosci. 1998 Aug;11(5-6):247-59
references: 9698392
references: J Vet Pharmacol Ther. 2012 Aug;35(4):413-6
references: 22132770
references: Cell Tissue Res. 1999 Oct;298(1):1-9
references: 10502115
references: Brain Res. 1975 Aug 15;93(3):485-9
references: 1182020
references: Nat Rev Mol Cell Biol. 2005 Jun;6(6):462-75
references: 15928710
references: J Cell Biol. 2005 Jul 18;170(2):285-94
references: 16027224
references: Neuron. 2008 Jul 10;59(1):56-69
references: 18614029
references: Gene Expr Patterns. 2003 Aug;3(4):437-40
references: 12915308
references: Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18202-7
references: 17110436
references: Mol Cell Neurosci. 1996 Feb;7(2):102-15
references: 8731479
references: J Neurochem. 1996 Jul;67(1):194-200
references: 8666992
references: Science. 2002 Dec 6;298(5600):1959-64
references: 12471249
references: Nat Med. 2006 Mar;12(3):348-53
references: 16491086
references: Science. 2002 Jan 18;295(5554):491-5
references: 11799243
references: Nat Neurosci. 2003 Feb;6(2):153-60
references: 12496762
references: Trends Neurosci. 2002 Mar;25(3):145-9
references: 11852146
references: Nat Neurosci. 2011 Feb;14(2):181-9
references: 21186356
references: Nat Neurosci. 1998 Jul;1(3):185-91
references: 10195142
references: Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12524-9
references: 19592509
references: Nat Neurosci. 2004 May;7(5):417-8
references: 15114347
references: Mol Pharmacol. 2007 Oct;72(4):907-20
references: 17622578
references: J Microsc. 2006 Dec;224(Pt 3):213-32
references: 17210054
references: Cell Adh Migr. 2007 Apr-Jun;1(2):110-2
references: 19270534
references: Science. 1994 Nov 4;266(5186):816-9
references: 7973638
references: Genes Dev. 1999 Dec 1;13(23):3125-35
references: 10601038
references: Mol Ther. 2009 Aug;17(8):1316-32
references: 19491821
references: J Comp Neurol. 2003 Feb 10;456(3):203-16
references: 12528186
references: J Neurochem. 2001 Aug;78(4):715-26
references: 11520892
references: Mol Cancer Res. 2002 Nov;1(1):79-87
references: 12496371
references: Lang Learn Dev. 2011 Jul;7(1):169-184
references: 22096450
references: J Exp Med. 2000 Feb 7;191(3):463-74
references: 10662792
references: Nat Neurosci. 2003 Mar;6(3):231-42
references: 12577062
references: Biochem Biophys Res Commun. 2002 Aug 9;296(1):214-20
references: 12147253
references: Curr Opin Cell Biol. 1997 Oct;9(5):608-15
references: 9330863
references: J Neurosci. 1995 Jan;15(1 Pt 1):1-11
references: 7823120
references: Neuron. 2000 Jun;26(3):659-70
references: 10896161