Excessive Na+/H+ exchange in disruption of dendritic Na+ and Ca2+ homeostasis and mitochondrial dysfunction following in vitro ischemia.
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.
Kintner
Douglas B
DB
Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705, USA.
Chen
Xinzhi
X
Currie
Julia
J
Chanana
Vishal
V
Ferrazzano
Peter
P
Baba
Akemichi
A
Matsuda
Toshio
T
Cohen
Mike
M
Orlowski
John
J
Chiu
Shing-Yan
SY
Taunton
Jack
J
Sun
Dandan
D
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*
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
Exp Neurol. 1998 Nov;154(1):241-58
9875285
J Neurosci. 2001 Jun 15;21(12):4225-36
11404408
Curr Drug Targets Cardiovasc Haematol Disord. 2005 Aug;5(4):323-35
16101565
J Biol Chem. 2004 Feb 27;279(9):7544-53
14660663
Am J Physiol Gastrointest Liver Physiol. 2002 Oct;283(4):G975-85
12223358
Basic Res Cardiol. 2001 Jul;96(4):306-11
11518185
Neuroscience. 1997 Jul;79(2):591-603
9200742
Am J Physiol Cell Physiol. 2007 Mar;292(3):C1113-22
17035299
Hippocampus. 2007;17(11):1049-59
17598158
J Neurosci. 2008 Feb 13;28(7):1756-72
18272696
IDrugs. 1999 Oct;2(10):1009-25
16118710
Mol Pharmacol. 2007 Mar;71(3):799-806
17142297
Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3517-23
17906113
J Neurosci. 1987 Feb;7(2):357-68
2880937
J Neurophysiol. 2000 Oct;84(4):1869-80
11024079
Neuroscience. 2001;102(1):217-28
11226686
Cell Calcium. 2007 Mar;41(3):221-34
16914199
J Neurosci. 2007 Jul 11;27(28):7438-46
17626204
Neurobiol Dis. 2007 Feb;25(2):284-90
17071096
J Mol Cell Cardiol. 2005 Jan;38(1):135-43
15623430
J Neurosci. 2005 Dec 7;25(49):11256-68
16339021
J Appl Physiol (1985). 2008 Dec;105(6):1706-13
18801963
Am J Physiol Cell Physiol. 2004 Jul;287(1):C12-21
15013953
Glia. 2002 Mar 15;37(4):365-73
11870875
Physiology (Bethesda). 2008 Apr;23:84-94
18400691
J Neurosci. 2004 Dec 8;24(49):11057-69
15590922
Brain Res. 1994 Mar 28;641(1):57-64
8019852
Biochem J. 2007 Jan 1;401(1):29-38
17040210
Integr Biol (Camb). 2010 Jan;2(1):58-64
20473413
J Biol Chem. 2007 Sep 7;282(36):26235-44
17616519
Science. 2005 May 27;308(5726):1318-21
15919995
Cell Calcium. 2008 Jul;44(1):51-63
18242694
Neuroreport. 2001 Aug 28;12(12):2731-5
11522957
Neurobiol Dis. 1996;3(3):215-27
8980022
Glia. 1993 Dec;9(4):280-91
8112821
J Neurosci. 2008 May 7;28(19):5029-39
18463256
J Neurochem. 2008 Aug;106(4):1563-76
18507737
J Biochem. 1990 Oct;108(4):689-93
2149857
J Biol Chem. 2007 Sep 21;282(38):28274-84
17664275
J Biol Chem. 2004 Aug 27;279(35):37115-23
15192115
Circulation. 2003 Nov 4;108(18):2275-81
14568900
Neuropharmacology. 2007 Dec;53(8):891-8
18031769
J Biol Chem. 2006 May 26;281(21):14864-74
16551630
J Neurophysiol. 1999 Jun;81(6):2627-35
10368383
J Neurophysiol. 2001 Dec;86(6):2715-26
11731531