title: Excessive Na+/H+ exchange in disruption of dendritic Na+ and Ca2+ homeostasis and mitochondrial dysfunction following in vitro ischemia.
abstract: Neuronal dendrites are vulnerable to injury under diverse pathological conditions. However, the underlying mechanisms for dendritic Na(+) overload and the selective dendritic injury remain poorly understood. Our current study demonstrates that activation of NHE-1 (Na(+)/H(+) exchanger isoform 1) in dendrites presents a major pathway for Na(+) overload. Neuronal dendrites exhibited higher pH(i) regulation rates than soma as a result of a larger surface area/volume ratio. Following a 2-h oxygen glucose deprivation and a 1-h reoxygenation, NHE-1 activity was increased by ∼70-200% in dendrites. This elevation depended on activation of p90 ribosomal S6 kinase. Moreover, stimulation of NHE-1 caused dendritic Na(+)(i) accumulation, swelling, and a concurrent loss of Ca(2+)(i) homeostasis. The Ca(2+)(i) overload in dendrites preceded the changes in soma. Inhibition of NHE-1 or the reverse mode of Na(+)/Ca(2+) exchange prevented these changes. Mitochondrial membrane potential in dendrites depolarized 40 min earlier than soma following oxygen glucose deprivation/reoxygenation. Blocking NHE-1 activity not only attenuated loss of dendritic mitochondrial membrane potential and mitochondrial Ca(2+) homeostasis but also preserved dendritic membrane integrity. Taken together, our study demonstrates that NHE-1-mediated Na(+) entry and subsequent Na(+)/Ca(2+) exchange activation contribute to the selective dendritic vulnerability to in vitro ischemia.
authors.affiliation: Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kintner
authors.forename: Xinzhi
authors.initials: X
authors.lastname: Chen
authors.forename: Julia
authors.initials: J
authors.lastname: Currie
authors.forename: Vishal
authors.initials: V
authors.lastname: Chanana
authors.forename: Peter
authors.initials: P
authors.lastname: Ferrazzano
authors.forename: Akemichi
authors.initials: A
authors.lastname: Baba
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
authors.forename: Mike
authors.initials: M
authors.lastname: Cohen
authors.forename: John
authors.initials: J
authors.lastname: Orlowski
authors.forename: Shing-Yan
authors.initials: SY
authors.lastname: Chiu
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
authors.forename: Dandan
authors.initials: D
authors.lastname: Sun
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis; D006859:Hydrogen / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D017136:Ion Transport; D051379:Mice; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; C490997:Slc9a1 protein, mouse; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D006859:Hydrogen; D012964:Sodium; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D002118:Calcium
references.citation: Exp Neurol. 1998 Nov;154(1):241-58
references.pmid: 9875285
references.citation: J Neurosci. 2001 Jun 15;21(12):4225-36
references.pmid: 11404408
references.citation: Curr Drug Targets Cardiovasc Haematol Disord. 2005 Aug;5(4):323-35
references.pmid: 16101565
references.citation: J Biol Chem. 2004 Feb 27;279(9):7544-53
references.pmid: 14660663
references.citation: Am J Physiol Gastrointest Liver Physiol. 2002 Oct;283(4):G975-85
references.pmid: 12223358
references.citation: Basic Res Cardiol. 2001 Jul;96(4):306-11
references.pmid: 11518185
references.citation: Neuroscience. 1997 Jul;79(2):591-603
references.pmid: 9200742
references.citation: Am J Physiol Cell Physiol. 2007 Mar;292(3):C1113-22
references.pmid: 17035299
references.citation: Hippocampus. 2007;17(11):1049-59
references.pmid: 17598158
references.citation: J Neurosci. 2008 Feb 13;28(7):1756-72
references.pmid: 18272696
references.citation: IDrugs. 1999 Oct;2(10):1009-25
references.pmid: 16118710
references.citation: Mol Pharmacol. 2007 Mar;71(3):799-806
references.pmid: 17142297
references.citation: Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3517-23
references.pmid: 17906113
references.citation: J Neurosci. 1987 Feb;7(2):357-68
references.pmid: 2880937
references.citation: J Neurophysiol. 2000 Oct;84(4):1869-80
references.pmid: 11024079
references.citation: Neuroscience. 2001;102(1):217-28
references.pmid: 11226686
references.citation: Cell Calcium. 2007 Mar;41(3):221-34
references.pmid: 16914199
references.citation: J Neurosci. 2007 Jul 11;27(28):7438-46
references.pmid: 17626204
references.citation: Neurobiol Dis. 2007 Feb;25(2):284-90
references.pmid: 17071096
references.citation: J Mol Cell Cardiol. 2005 Jan;38(1):135-43
references.pmid: 15623430
references.citation: J Neurosci. 2005 Dec 7;25(49):11256-68
references.pmid: 16339021
references.citation: J Appl Physiol (1985). 2008 Dec;105(6):1706-13
references.pmid: 18801963
references.citation: Am J Physiol Cell Physiol. 2004 Jul;287(1):C12-21
references.pmid: 15013953
references.citation: Glia. 2002 Mar 15;37(4):365-73
references.pmid: 11870875
references.citation: Physiology (Bethesda). 2008 Apr;23:84-94
references.pmid: 18400691
references.citation: J Neurosci. 2004 Dec 8;24(49):11057-69
references.pmid: 15590922
references.citation: Brain Res. 1994 Mar 28;641(1):57-64
references.pmid: 8019852
references.citation: Biochem J. 2007 Jan 1;401(1):29-38
references.pmid: 17040210
references.citation: Integr Biol (Camb). 2010 Jan;2(1):58-64
references.pmid: 20473413
references.citation: J Biol Chem. 2007 Sep 7;282(36):26235-44
references.pmid: 17616519
references.citation: Science. 2005 May 27;308(5726):1318-21
references.pmid: 15919995
references.citation: Cell Calcium. 2008 Jul;44(1):51-63
references.pmid: 18242694
references.citation: Neuroreport. 2001 Aug 28;12(12):2731-5
references.pmid: 11522957
references.citation: Neurobiol Dis. 1996;3(3):215-27
references.pmid: 8980022
references.citation: Glia. 1993 Dec;9(4):280-91
references.pmid: 8112821
references.citation: J Neurosci. 2008 May 7;28(19):5029-39
references.pmid: 18463256
references.citation: J Neurochem. 2008 Aug;106(4):1563-76
references.pmid: 18507737
references.citation: J Biochem. 1990 Oct;108(4):689-93
references.pmid: 2149857
references.citation: J Biol Chem. 2007 Sep 21;282(38):28274-84
references.pmid: 17664275
references.citation: J Biol Chem. 2004 Aug 27;279(35):37115-23
references.pmid: 15192115
references.citation: Circulation. 2003 Nov 4;108(18):2275-81
references.pmid: 14568900
references.citation: Neuropharmacology. 2007 Dec;53(8):891-8
references.pmid: 18031769
references.citation: J Biol Chem. 2006 May 26;281(21):14864-74
references.pmid: 16551630
references.citation: J Neurophysiol. 1999 Jun;81(6):2627-35
references.pmid: 10368383
references.citation: J Neurophysiol. 2001 Dec;86(6):2715-26
references.pmid: 11731531