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Hierarchical recruitment by AMPA but not staurosporine of pro-apoptotic mitochondrial signaling in cultured cortical neurons: evidence for caspase-dependent/independent cross-talk.
J Neurochem. 2007 Dec; 103(6):2408-27.JN

Abstract

Excitotoxicity mediated via the (S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) subtype of receptor for l-glutamate contributes to various neuropathologies involving acute brain injury and chronic degenerative disorders. In this study, AMPA-induced neuronal injury and staurosporine (STS)-mediated apoptosis were compared in primary neuronal cultures of murine cerebral cortex by analyzing indices up- and downstream of mitochondrial activation. AMPA-mediated apoptosis involved induction of Bax, loss of mitochondrial transmembrane potential (deltapsi(m)), early release of cytochrome c (cyt c), and more delayed release of second mitochondrial activator of caspases (SMAC), Omi, and apoptosis-inducing factor (AIF) with early calpain and minor late activation of caspase 3. STS-induced apoptosis was characterized by a number of differences, a more rapid time course, non-involvement of deltapsi(m), and relatively early recruitment of SMAC and caspase 3. The AMPA-induced rise in intracellular calcium appeared insufficient to evoke feltapsi(m) as release of cyt c preceded mitochondrial depolarization, which was followed by the cytosolic translocation of SMAC, Omi, and AIF. Bax translocation preceded cyt c release for both stimuli inferring its involvement in apoptotic induction. Inclusion of the broad spectrum caspase inhibitor zVAD-fmk reduced the AMPA-induced release of cyt c, SMAC, and AIF, while only affecting the redistribution of Omi and AIF in the STS-treated neurons. Only AIF release was affected by a calpain inhibitor (calpastatin) which exerted relatively minor effects on the progression of cellular injury. AMPA-mediated release of apoptogenic proteins was more hierarchical relative to STS with its calpain activation and caspase-dependent AIF redistribution arguing for a model with cross-talk between caspase-dependent/independent apoptosis.

Authors+Show Affiliations

Brain Injury and Repair Program, Howard Florey Institute, University of Melbourne, Parkville, Victoria, Australia. p.beart@hfi.unimelb.edu.auNo 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

17887970

Citation

Beart, Philip M., et al. "Hierarchical Recruitment By AMPA but Not Staurosporine of Pro-apoptotic Mitochondrial Signaling in Cultured Cortical Neurons: Evidence for Caspase-dependent/independent Cross-talk." Journal of Neurochemistry, vol. 103, no. 6, 2007, pp. 2408-27.
Beart PM, Lim ML, Chen B, et al. Hierarchical recruitment by AMPA but not staurosporine of pro-apoptotic mitochondrial signaling in cultured cortical neurons: evidence for caspase-dependent/independent cross-talk. J Neurochem. 2007;103(6):2408-27.
Beart, P. M., Lim, M. L., Chen, B., Diwakarla, S., Mercer, L. D., Cheung, N. S., & Nagley, P. (2007). Hierarchical recruitment by AMPA but not staurosporine of pro-apoptotic mitochondrial signaling in cultured cortical neurons: evidence for caspase-dependent/independent cross-talk. Journal of Neurochemistry, 103(6), 2408-27.
Beart PM, et al. Hierarchical Recruitment By AMPA but Not Staurosporine of Pro-apoptotic Mitochondrial Signaling in Cultured Cortical Neurons: Evidence for Caspase-dependent/independent Cross-talk. J Neurochem. 2007;103(6):2408-27. PubMed PMID: 17887970.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hierarchical recruitment by AMPA but not staurosporine of pro-apoptotic mitochondrial signaling in cultured cortical neurons: evidence for caspase-dependent/independent cross-talk. AU - Beart,Philip M, AU - Lim,Maria L R, AU - Chen,Baohong, AU - Diwakarla,Shanti, AU - Mercer,Linda D, AU - Cheung,Nam Sang, AU - Nagley,Phillip, Y1 - 2007/09/20/ PY - 2007/9/25/pubmed PY - 2008/1/9/medline PY - 2007/9/25/entrez SP - 2408 EP - 27 JF - Journal of neurochemistry JO - J Neurochem VL - 103 IS - 6 N2 - Excitotoxicity mediated via the (S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) subtype of receptor for l-glutamate contributes to various neuropathologies involving acute brain injury and chronic degenerative disorders. In this study, AMPA-induced neuronal injury and staurosporine (STS)-mediated apoptosis were compared in primary neuronal cultures of murine cerebral cortex by analyzing indices up- and downstream of mitochondrial activation. AMPA-mediated apoptosis involved induction of Bax, loss of mitochondrial transmembrane potential (deltapsi(m)), early release of cytochrome c (cyt c), and more delayed release of second mitochondrial activator of caspases (SMAC), Omi, and apoptosis-inducing factor (AIF) with early calpain and minor late activation of caspase 3. STS-induced apoptosis was characterized by a number of differences, a more rapid time course, non-involvement of deltapsi(m), and relatively early recruitment of SMAC and caspase 3. The AMPA-induced rise in intracellular calcium appeared insufficient to evoke feltapsi(m) as release of cyt c preceded mitochondrial depolarization, which was followed by the cytosolic translocation of SMAC, Omi, and AIF. Bax translocation preceded cyt c release for both stimuli inferring its involvement in apoptotic induction. Inclusion of the broad spectrum caspase inhibitor zVAD-fmk reduced the AMPA-induced release of cyt c, SMAC, and AIF, while only affecting the redistribution of Omi and AIF in the STS-treated neurons. Only AIF release was affected by a calpain inhibitor (calpastatin) which exerted relatively minor effects on the progression of cellular injury. AMPA-mediated release of apoptogenic proteins was more hierarchical relative to STS with its calpain activation and caspase-dependent AIF redistribution arguing for a model with cross-talk between caspase-dependent/independent apoptosis. SN - 1471-4159 UR - https://www.unboundmedicine.com/medline/citation/17887970/Hierarchical_recruitment_by_AMPA_but_not_staurosporine_of_pro_apoptotic_mitochondrial_signaling_in_cultured_cortical_neurons:_evidence_for_caspase_dependent/independent_cross_talk_ L2 - https://doi.org/10.1111/j.1471-4159.2007.04937.x DB - PRIME DP - Unbound Medicine ER -