Carbon monoxide protects against oxidant-induced apoptosis via inhibition of Kv2.1.
Oxidative stress induces neuronal apoptosis and is implicated in cerebral ischemia, head trauma, and age-related neurodegenerative diseases. An early step in this process is the loss of intracellular K(+) via K(+) channels, and evidence indicates that K(v)2.1 is of particular importance in this regard, being rapidly inserted into the plasma membrane in response to apoptotic stimuli. An additional feature of neuronal oxidative stress is the up-regulation of the inducible enzyme heme oxygenase-1 (HO-1), which catabolizes heme to generate biliverdin, Fe(2+), and carbon monoxide (CO). CO provides neuronal protection against stresses such as stroke and excitotoxicity, although the underlying mechanisms are not yet elucidated. Here, we demonstrate that CO reversibly inhibits K(v)2.1. Channel inhibition by CO involves reactive oxygen species and protein kinase G activity. Overexpression of K(v)2.1 in HEK293 cells increases their vulnerability to oxidant-induced apoptosis, and this is reversed by CO. In hippocampal neurons, CO selectively inhibits K(v)2.1, reverses the dramatic oxidant-induced increase in K(+) current density, and provides marked protection against oxidant-induced apoptosis. Our results provide a novel mechanism to account for the neuroprotective effects of CO against oxidative apoptosis, which has potential for therapeutic exploitation to provide neuronal protection in situations of oxidative stress.
Division of Cardiovascular and Neuronal Remodelling, Faculty of Medicine and Health, University of Leeds, Leeds, UK.
Mark L
ML
Dallas
John P
JP
Boyle
Carol J
CJ
Milligan
Rachael
R
Sayer
Talitha L
TL
Kerrigan
Connor
C
McKinstry
Peiyuan
P
Lu
Jamel
J
Mankouri
Mark
M
Harris
Jason L
JL
Scragg
Hugh A
HA
Pearson
Chris
C
Peers
D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002248:Carbon Monoxide / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D004220:Disulfides / Q000494:pharmacology*; D004594:Electrophysiology; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D016877:Oxidants / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D051669:Shab Potassium Channels / Q000378:metabolism*
D004220:Disulfides; D016877:Oxidants; D051669:Shab Potassium Channels; C001105:2,2'-dipyridyl disulfide; D015082:2,2'-Dipyridyl; D002248:Carbon Monoxide; D053148:Caspase 3; D053179:Caspase 7
Learn Mem. 2008 Oct 02;15(10):792-805
18832566
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3568-73
17360683
Antioxid Redox Signal. 2007 May;9(5):543-52
17330989
Neuron. 2004 Feb 5;41(3):351-65
14766175
Science. 2004 Dec 17;306(5704):2093-7
15528406
Annu Rev Pharmacol Toxicol. 2002;42:259-81
11807173
J Biol Chem. 1997 Nov 28;272(48):30567-76
9374553
J Neurosci. 1999 Mar 1;19(5):1728-35
10024359
Neurobiol Aging. 2006 Nov;27(11):1673-83
16271805
Mol Med. 1999 Oct;5(10):656-63
10602774
Neuroscience. 2000;99(4):587-92
10974422
Neuroscience. 1998 May;84(1):37-48
9522360
Nat Rev Mol Cell Biol. 2007 Sep;8(9):722-8
17700625
Int Rev Neurobiol. 2007;82:297-325
17678968
Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12351-6
20566856
J Cell Sci. 2009 Mar 15;122(Pt 6):775-9
19223394
J Clin Invest. 2008 Jan;118(1):239-47
18060048
Neuroreport. 2008 Feb 12;19(3):345-8
18303579
Circ Res. 2005 Oct 14;97(8):805-12
16166559
Mol Pharmacol. 2003 Jun;63(6):1322-8
12761342
J Neurochem. 2009 May;109 Suppl 1:133-8
19393019
Aging Cell. 2007 Jun;6(3):361-70
17517043
Am J Pathol. 1998 Apr;152(4):871-7
9546346
Curr Top Cell Regul. 2000;36:181-99
10842752
Curr Opin Cell Biol. 2001 Aug;13(4):405-11
11454444
Biochem Biophys Res Commun. 2005 Jun 17;331(4):993-1000
15882976
Circ Res. 2002 Sep 20;91(6):478-86
12242265
Exp Neurol. 2009 Aug;218(2):371-80
19427308
J Neurosci. 2006 Dec 27;26(52):13505-14
17192433
Cell Death Differ. 2006 Apr;13(4):661-7
16273079
Trends Cell Biol. 2010 Jan;20(1):45-51
19850480
Science. 2006 Aug 18;313(5789):976-9
16917065
Nat Cell Biol. 1999 Jul;1(3):152-7
10559901
FASEB J. 2007 Apr;21(4):1099-106
17264172
Antioxid Redox Signal. 2007 Aug;9(8):1059-96
17571960
J Neurochem. 2009 Jul;110(2):469-85
19457088
Neurotox Res. 2009 Feb;15(2):133-7
19384576
Pharmacol Rev. 2005 Dec;57(4):585-630
16382109
J Biol Chem. 2008 Sep 5;283(36):24412-9
18596041
J Neurosci. 2010 Apr 21;30(16):5677-89
20410120
Science. 1997 Oct 3;278(5335):114-7
9311914
Prog Neurobiol. 2003 Jul;70(4):363-86
12963093
Neuroscience. 2006 Sep 15;141(4):1703-8
16828975
Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11796-800
8524851
J Neurochem. 2000 Nov;75(5):1878-88
11032877
Int Rev Cytol. 2002;221:93-148
12455747
Stroke. 2003 May;34(5):1281-6
12677023
J Neurosci. 2003 Jun 15;23(12):4798-802
12832499
Nat Rev Drug Discov. 2010 Sep;9(9):728-43
20811383
Annu Rev Pharmacol Toxicol. 2006;46:411-49
16402911