title: Voltage-gated sodium channel Nav 1.5 contributes to astrogliosis in an in vitro model of glial injury via reverse Na+ /Ca2+ exchange.
abstract: Astrogliosis is a prominent feature of many, if not all, pathologies of the brain and spinal cord, yet a detailed understanding of the underlying molecular pathways involved in the transformation from quiescent to reactive astrocyte remains elusive. We investigated the contribution of voltage-gated sodium channels to astrogliosis in an in vitro model of mechanical injury to astrocytes. Previous studies have shown that a scratch injury to astrocytes invokes dual mechanisms of migration and proliferation in these cells. Our results demonstrate that wound closure after mechanical injury, involving both migration and proliferation, is attenuated by pharmacological treatment with tetrodotoxin (TTX) and KB-R7943, at a dose that blocks reverse mode of the Na(+) /Ca(2+) exchanger (NCX), and by knockdown of Nav 1.5 mRNA. We also show that astrocytes display a robust [Ca(2+) ]i transient after mechanical injury and demonstrate that this [Ca(2+) ]i response is also attenuated by TTX, KB-R7943, and Nav 1.5 mRNA knockdown. Our results suggest that Nav 1.5 and NCX are potential targets for modulation of astrogliosis after injury via their effect on [Ca(2+) ]i .
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut; Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, Connecticut.
authors.forename: Laura W
authors.initials: LW
authors.lastname: Pappalardo
authors.forename: Omar A
authors.initials: OA
authors.lastname: Samad
authors.forename: Joel A
authors.initials: JA
authors.lastname: Black
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex; D055785:Gene Knockdown Techniques; D005911:Gliosis / Q000188:drug therapy / Q000503:physiopathology*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D010812:Physical Stimulation; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology; D014947:Wounds and Injuries / Q000188:drug therapy / Q000503:physiopathology*
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D062554:NAV1.5 Voltage-Gated Sodium Channel; D012333:RNA, Messenger; D026941:Sodium Channel Blockers; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D013779:Tetrodotoxin; D013890:Thiourea; D002118:Calcium
keywords: glial scar; migration; proliferation; sodium channels; sodium-calcium exchanger
references.citation: Exp Neurol. 2004 Aug;188(2):365-77
references.pmid: 15246836
references.citation: J Neurosci. 2013 Jul 31;33(31):12870-86
references.pmid: 23904622
references.citation: Glia. 2013 Aug;61(8):1191-205
references.pmid: 23553639
references.citation: J Biol Chem. 1996 Sep 13;271(37):22391-7
references.pmid: 8798401
references.citation: J Immunol. 2009 Mar 1;182(5):2628-40
references.pmid: 19234157
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 12;101(41):14937-42
references.pmid: 15466714
references.citation: ASN Neuro. 2012 Jan 23;4(1):
references.pmid: 22268447
references.citation: Neuron. 2008 Sep 25;59(6):932-46
references.pmid: 18817732
references.citation: FEMS Immunol Med Microbiol. 2011 Dec;63(3):319-27
references.pmid: 22092558
references.citation: Pharmacol Rev. 2005 Dec;57(4):397-409
references.pmid: 16382098
references.citation: Exp Neurol. 2012 Apr;234(2):302-15
references.pmid: 21985863
references.citation: J Biol Chem. 2009 Mar 27;284(13):8680-91
references.pmid: 19176528
references.citation: Bioessays. 1995 Jun;17(6):491-500
references.pmid: 7575490
references.citation: J Biol Chem. 2009 Mar 20;284(12):8114-26
references.pmid: 19136557
references.citation: Glia. 1995 Oct;15(2):119-30
references.pmid: 8567063
references.citation: FEBS Lett. 2004 Jul 2;569(1-3):191-4
references.pmid: 15225632
references.citation: J Neuroinflammation. 2010 Nov 24;7:84
references.pmid: 21092323
references.citation: J Cell Biol. 2009 Jul 13;186(1):113-28
references.pmid: 19596850
references.citation: J Neurophysiol. 1997 Jan;77(1):236-46
references.pmid: 9120565
references.citation: Physiol Rev. 2012 Oct;92(4):1865-913
references.pmid: 23073633
references.citation: Hippocampus. 1994 Jun;4(3):297-306
references.pmid: 7842053
references.citation: J Neurosci Res. 2000 Aug 15;61(4):421-9
references.pmid: 10931528
references.citation: J Neurophysiol. 1998 Apr;79(4):2222-6
references.pmid: 9535982
references.citation: Neuron. 2013 Oct 16;80(2):280-91
references.pmid: 24139034
references.citation: J Exp Med. 2005 Jul 4;202(1):145-56
references.pmid: 15998793
references.citation: Brain. 2013 Apr;136(Pt 4):1067-82
references.pmid: 23518709
references.citation: Ann Neurol. 2007 Jul;62(1):21-33
references.pmid: 17654737
references.citation: Cell Calcium. 2007 Mar;41(3):221-34
references.pmid: 16914199
references.citation: J Neurosci. 2012 May 2;32(18):6391-410
references.pmid: 22553043
references.citation: J Neurochem. 1992 Apr;58(4):1277-84
references.pmid: 1548464
references.citation: J Neurosci. 2004 Mar 3;24(9):2143-55
references.pmid: 14999065
references.citation: Glia. 2005 Jul;51(1):35-46
references.pmid: 15779085
references.citation: Nat Med. 2006 Jul;12(7):829-34
references.pmid: 16783372
references.citation: Nat Rev Neurosci. 2009 Mar;10(3):235-41
references.pmid: 19229242
references.citation: Nat Rev Neurosci. 2004 Feb;5(2):146-56
references.pmid: 14735117
references.citation: Glia. 1998 Jul;23(3):200-8
references.pmid: 9633805
references.citation: Trends Neurosci. 2009 Dec;32(12):638-47
references.pmid: 19782411
references.citation: Mol Ther. 2013 Jan;21(1):49-56
references.pmid: 22910296
references.citation: J Cell Physiol. 2003 Jun;195(3):479-87
references.pmid: 12704658
references.citation: Breast Cancer Res Treat. 2007 Jan;101(2):149-60
references.pmid: 16838113
references.citation: Trends Neurosci. 2012 Aug;35(8):497-506
references.pmid: 22633141
references.citation: Nat Immunol. 2012 Sep;13(9):880-7
references.pmid: 22842345
references.citation: Brain. 2010 Mar;133(Pt 3):835-46
references.pmid: 20147455
references.citation: Transl Neurosci. 2012 Dec;3(4):334-344
references.pmid: 23243501
references.citation: J Neurochem. 2007 Nov;103(3):1196-207
references.pmid: 17935604
references.citation: Proc Natl Acad Sci U S A. 1989 Oct;86(20):8170-4
references.pmid: 2554302
references.citation: Glia. 1999 Mar;26(1):92-6
references.pmid: 10088676
references.citation: Glia. 2006 Nov 15;54(7):758-73
references.pmid: 17006904
references.citation: Trends Neurosci. 1996 Aug;19(8):325-31
references.pmid: 8843601
references.citation: J Neurosci. 2013 Apr 24;33(17):7206-19
references.pmid: 23616530
references.citation: Glia. 1994 Nov;12(3):219-27
references.pmid: 7851989
references.citation: Mol Cell Biochem. 2008 Jan;308(1-2):219-26
references.pmid: 17978865
references.citation: Exp Cell Res. 1999 Feb 1;246(2):319-26
references.pmid: 9925747
references.citation: J Neurol. 2006 Dec;253(12):1542-51
references.pmid: 17219031
references.citation: J Neurosci. 2008 Jul 9;28(28):7231-43
references.pmid: 18614693
references.citation: J Cell Physiol. 2006 May;207(2):437-44
references.pmid: 16331678
references.citation: J Neurosci Res. 1993 Feb 15;34(3):295-303
references.pmid: 8455207
references.citation: J Immunol. 2011 Aug 1;187(3):1273-80
references.pmid: 21715690
references.citation: FASEB J. 1997 Jun;11(7):566-72
references.pmid: 9212080
references.citation: J Neurosci. 2013 Dec 4;33(49):19250-61
references.pmid: 24305821
references.citation: Cancer Res. 2010 Sep 1;70(17):6957-67
references.pmid: 20651255
references.citation: Ann Neurol. 2013 Jan;73(1):140-5
references.pmid: 23280954
references.citation: J Clin Neurosci. 2007 Jul;14(7):658-65
references.pmid: 17532502
references.citation: J Physiol. 2004 Oct 1;560(Pt 1):37-49
references.pmid: 15272045
references.citation: Glia. 2013 Dec;61(12):2063-77
references.pmid: 24123203