title: Protective effects of SKF-96365, a non-specific inhibitor of SOCE, against MPP+-induced cytotoxicity in PC12 cells: potential role of Homer1.
abstract: Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized by loss of dopominergic (DA) neurons in substantia nigra pars compacta (SNpc), and can be experimentally mimicked by the neurotoxin MPP(+) in vitro models. In this study, we investigated the potential protective effect of SKF-96365, a non-specific inhibitor of SOCE (store-operated calcium entry), on MPP(+) induced cytotoxicity in PC12 cells. We found that pretreatment with SKF-96365 (10 µM and 50 µM) 30 min before injury significantly increased cell viability, decreased LDH release, prevented nuclear damage, and inhibited apoptotic cell death in MPP(+) stressed PC12 cells. The results of calcium image using the ratiometric calcium indicator Fura-2-AM also showed that SKF-96365 reduced the intracellular calcium overload induced by MPP(+) in PC12 cells. In addition, SKF-96365 decreased the expression of Homer1, a more recently discovered postsynaptic scaffolding protein with calcium modulating function, following MPP(+) administration in PC12 cells, while had no statistically significant effects on endoplasmic reticulum (ER) calcium concentration. Furthermore, overexpression of Homer1 by using recombinant lentivirus partly reversed protective effects of SKF-96365 against MPP(+) injury. The ER Ca(2+) release was further amplified and ER calcium recovery was delayed by Homer1 upregulation in PC12 cells following MPP(+) insult. Taken together, these data suggest that SKF-96365 protects PC12 cells against MPP(+) induced cytotoxicity, and this protection may be at least in part on the inhibition of intracellular calcium overload and suppression of Homer1-mediated ER Ca(2+) release.
authors: Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Tao
authors: T
authors: Chen
authors: Jie
authors: J
authors: Zhu
authors: Chi
authors: C
authors: Zhang
authors: Kai
authors: K
authors: Huo
authors: Zhou
authors: Z
authors: Fei
authors: Xiao-fan
authors: XF
authors: Jiang
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D000072233:Homer Scaffolding Proteins; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats
chemical_list: D002352:Carrier Proteins; C000606614:HOMER1 protein, human; D000072233:Homer Scaffolding Proteins; C000606624:Homer1 protein, rat; D007093:Imidazoles; D018696:Neuroprotective Agents; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D015655:1-Methyl-4-phenylpyridinium; D002118:Calcium
references: Physiol Rev. 2005 Apr;85(2):757-810
references: 15788710
references: Apoptosis. 2012 Sep;17(9):975-88
references: 22660975
references: Free Radic Biol Med. 2012 Jan 1;52(1):208-17
references: 22080088
references: NeuroRx. 2004 Jan;1(1):139-54
references: 15717014
references: Neuron. 1998 Oct;21(4):717-26
references: 9808459
references: Annu Rev Physiol. 1989;51:491-506
references: 2653192
references: Neurosci Lett. 2012 Apr 25;515(1):44-9
references: 22445886
references: Br J Pharmacol. 2010 Jul;160(6):1464-75
references: 20590636
references: Neuroscience. 2011 Dec 15;198:221-31
references: 21884755
references: Curr Opin Neurobiol. 2000 Jun;10(3):370-4
references: 10851183
references: Neurosci Bull. 2012 Apr;28(2):173-81
references: 22466128
references: J Biol Chem. 1998 Apr 24;273(17):10279-87
references: 9553080
references: Science. 2003 Oct 31;302(5646):819-22
references: 14593166
references: PLoS One. 2009 Aug 21;4(8):e6723
references: 19696927
references: Neuroscience. 2011 Jan 13;172:387-97
references: 21044663
references: J Neurosci. 2001 Jun 1;21(11):3797-805
references: 11356868
references: EMBO J. 1995 Feb 15;14(4):736-42
references: 7882977
references: J Cell Physiol. 2012 Apr;227(4):1485-92
references: 21618539
references: J Cell Biol. 2003 Jul 21;162(2):293-303
references: 12860966
references: Nature. 1997 Mar 20;386(6622):284-8
references: 9069287
references: Biochim Biophys Acta. 1985 Oct 30;847(1):101-7
references: 2864958
references: Annu Rev Physiol. 2006;68:619-47
references: 16460286
references: Neurology. 2008 Apr 15;70(16 Pt 2):1438-44
references: 18256367
references: Cell. 2003 Sep 19;114(6):777-89
references: 14505576
references: Adv Neurol. 2001;86:55-72
references: 11554010
references: Int J Mol Med. 2011 Aug;28(2):161-9
references: 21537829
references: Biofactors. 2011 May-Jun;37(3):228-40
references: 21674642
references: Mov Disord. 2008;23 Suppl 3:S521-33
references: 18781679
references: Neurobiol Aging. 2003 Mar-Apr;24(2):197-211
references: 12498954
references: Free Radic Biol Med. 2008 Jun 1;44(11):1960-9
references: 18395527
references: Cold Spring Harb Perspect Biol. 2011 Jun 01;3(6):
references: 21441595
references: Ann Neurol. 2010 May;67(5):600-6
references: 20437557
references: Neurology. 2007 Jan 30;68(5):384-6
references: 17082464
references: Free Radic Biol Med. 2011 Feb 1;50(3):469-76
references: 21145388
references: Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17510-5
references: 15576511
references: Biochem J. 1990 Oct 15;271(2):515-22
references: 2173565
references: Neurology. 2008 Aug 12;71(7):470-1
references: 18695156
references: Mol Cell Neurosci. 2002 Jun;20(2):323-9
references: 12093163
references: Exp Cell Res. 1999 Jul 10;250(1):75-85
references: 10388522
references: Nature. 2005 Apr 14;434(7035):898-904
references: 15758951
references: JAMA. 2004 Jan 21;291(3):358-64
references: 14734599
references: J Biol Chem. 1998 Jan 2;273(1):133-42
references: 9417057
references: Biochem Pharmacol. 2003 Feb 1;65(3):329-38
references: 12527326
references: Neurobiol Dis. 2011 Aug;43(2):364-71
references: 21515375