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Changes in calcium dynamics following the reversal of the sodium-calcium exchanger have a key role in AMPA receptor-mediated neurodegeneration via calpain activation in hippocampal neurons

Araujo, I. M.; Carreira, B. P.; Pereira, T.; Santos, P. F.; Soulet, Denis LU ; Inacio, A.; Bahr, B. A.; Carvalho, A. P.; Ambrosio, A. F. and Carvalho, C. M. (2007) In Cell Death and Differentiation 14(9). p.1635-1646
Abstract
Proteolytic cleavage of the Na+/Ca2+ exchanger (NCX) by calpains impairs calcium homeostasis, leading to a delayed calcium overload and excitotoxic cell death. However, it is not known whether reversal of the exchanger contributes to activate calpains and trigger neuronal death. We investigated the role of the reversal of the NCX in Ca2+ dynamics, calpain activation and cell viability, in alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-stimulated hippocampal neurons. Selective overactivation of AMPA receptors caused the reversal of the NCX, which accounted for approximately 30% of the rise in intracellular free calcium concentration ([Ca2+](i)). The NCX reverse-mode inhibitor, 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl]... (More)
Proteolytic cleavage of the Na+/Ca2+ exchanger (NCX) by calpains impairs calcium homeostasis, leading to a delayed calcium overload and excitotoxic cell death. However, it is not known whether reversal of the exchanger contributes to activate calpains and trigger neuronal death. We investigated the role of the reversal of the NCX in Ca2+ dynamics, calpain activation and cell viability, in alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-stimulated hippocampal neurons. Selective overactivation of AMPA receptors caused the reversal of the NCX, which accounted for approximately 30% of the rise in intracellular free calcium concentration ([Ca2+](i)). The NCX reverse-mode inhibitor, 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl] isothiourea (KB-R7943), partially inhibited the initial increase in [Ca2+](i), and prevented a delayed increase in [Ca2+](i). In parallel, overactivation of AMPA receptors strongly activated calpains and led to the proteolysis of NCX3. KB-R7943 prevented calpain activation, cleavage of NCX3 and was neuroprotective. Silencing of NCX3 reduced Ca2+ uptake, calpain activation and was neuroprotective. Our data show for the first time that NCX reversal is an early event following AMPA receptor stimulation and is linked to the activation of calpains. Since calpain activation subsequently inactivates NCX, causing a secondary Ca2+ entry, NCX may be viewed as a new suicide substrate operating in a Ca2+-dependent loop that triggers cell death and as a target for neuroprotection. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
sodium-calcium, proteolysis, calpains, excitotoxicity, calcium, AMPA receptors, exchanger
in
Cell Death and Differentiation
volume
14
issue
9
pages
1635 - 1646
publisher
Nature Publishing Group
external identifiers
  • wos:000248801700009
  • scopus:34548022118
ISSN
1350-9047
DOI
10.1038/sj.cdd.4402171
language
English
LU publication?
yes
id
264f2250-3070-4be1-be71-16eb7455dee2 (old id 692793)
date added to LUP
2007-12-06 12:17:30
date last changed
2017-05-28 03:41:28
@article{264f2250-3070-4be1-be71-16eb7455dee2,
  abstract     = {Proteolytic cleavage of the Na+/Ca2+ exchanger (NCX) by calpains impairs calcium homeostasis, leading to a delayed calcium overload and excitotoxic cell death. However, it is not known whether reversal of the exchanger contributes to activate calpains and trigger neuronal death. We investigated the role of the reversal of the NCX in Ca2+ dynamics, calpain activation and cell viability, in alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-stimulated hippocampal neurons. Selective overactivation of AMPA receptors caused the reversal of the NCX, which accounted for approximately 30% of the rise in intracellular free calcium concentration ([Ca2+](i)). The NCX reverse-mode inhibitor, 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl] isothiourea (KB-R7943), partially inhibited the initial increase in [Ca2+](i), and prevented a delayed increase in [Ca2+](i). In parallel, overactivation of AMPA receptors strongly activated calpains and led to the proteolysis of NCX3. KB-R7943 prevented calpain activation, cleavage of NCX3 and was neuroprotective. Silencing of NCX3 reduced Ca2+ uptake, calpain activation and was neuroprotective. Our data show for the first time that NCX reversal is an early event following AMPA receptor stimulation and is linked to the activation of calpains. Since calpain activation subsequently inactivates NCX, causing a secondary Ca2+ entry, NCX may be viewed as a new suicide substrate operating in a Ca2+-dependent loop that triggers cell death and as a target for neuroprotection.},
  author       = {Araujo, I. M. and Carreira, B. P. and Pereira, T. and Santos, P. F. and Soulet, Denis and Inacio, A. and Bahr, B. A. and Carvalho, A. P. and Ambrosio, A. F. and Carvalho, C. M.},
  issn         = {1350-9047},
  keyword      = {sodium-calcium,proteolysis,calpains,excitotoxicity,calcium,AMPA receptors,exchanger},
  language     = {eng},
  number       = {9},
  pages        = {1635--1646},
  publisher    = {Nature Publishing Group},
  series       = {Cell Death and Differentiation},
  title        = {Changes in calcium dynamics following the reversal of the sodium-calcium exchanger have a key role in AMPA receptor-mediated neurodegeneration via calpain activation in hippocampal neurons},
  url          = {http://dx.doi.org/10.1038/sj.cdd.4402171},
  volume       = {14},
  year         = {2007},
}