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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.
Cell Death Differ. 2007 Sep; 14(9):1635-46.CD

Abstract

Proteolytic cleavage of the Na(+)/Ca(2+) 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 Ca(2+) 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 ([Ca(2+)](i)). The NCX reverse-mode inhibitor, 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea (KB-R7943), partially inhibited the initial increase in [Ca(2+)](i), and prevented a delayed increase in [Ca(2+)](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 Ca(2+) 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 Ca(2+) entry, NCX may be viewed as a new suicide substrate operating in a Ca(2+)-dependent loop that triggers cell death and as a target for neuroprotection.

Authors+Show Affiliations

Center for Neuroscience and Cell Biology, Department of Zoology, University of Coimbra, Coimbra, Portugal. inaraujo@cnc.cj.uc.ptNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17585341

Citation

Araújo, I M., et al. "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." Cell Death and Differentiation, vol. 14, no. 9, 2007, pp. 1635-46.
Araújo IM, Carreira BP, Pereira T, et al. 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. Cell Death Differ. 2007;14(9):1635-46.
Araújo, I. M., Carreira, B. P., Pereira, T., Santos, P. F., Soulet, D., Inácio, A., Bahr, B. A., Carvalho, A. P., Ambrósio, A. F., & Carvalho, C. M. (2007). 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. Cell Death and Differentiation, 14(9), 1635-46.
Araújo IM, et al. 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. Cell Death Differ. 2007;14(9):1635-46. PubMed PMID: 17585341.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Araújo,I M, AU - Carreira,B P, AU - Pereira,T, AU - Santos,P F, AU - Soulet,D, AU - Inácio,A, AU - Bahr,B A, AU - Carvalho,A P, AU - Ambrósio,A F, AU - Carvalho,C M, Y1 - 2007/06/22/ PY - 2007/6/23/pubmed PY - 2007/12/7/medline PY - 2007/6/23/entrez SP - 1635 EP - 46 JF - Cell death and differentiation JO - Cell Death Differ VL - 14 IS - 9 N2 - Proteolytic cleavage of the Na(+)/Ca(2+) 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 Ca(2+) 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 ([Ca(2+)](i)). The NCX reverse-mode inhibitor, 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea (KB-R7943), partially inhibited the initial increase in [Ca(2+)](i), and prevented a delayed increase in [Ca(2+)](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 Ca(2+) 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 Ca(2+) entry, NCX may be viewed as a new suicide substrate operating in a Ca(2+)-dependent loop that triggers cell death and as a target for neuroprotection. SN - 1350-9047 UR - https://www.unboundmedicine.com/medline/citation/17585341/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_ L2 - https://doi.org/10.1038/sj.cdd.4402171 DB - PRIME DP - Unbound Medicine ER -