Tags

Type your tag names separated by a space and hit enter

CGP37157, an inhibitor of the mitochondrial Na+/Ca2+ exchanger, protects neurons from excitotoxicity by blocking voltage-gated Ca2+ channels.
Cell Death Dis. 2014 Apr 10; 5:e1156.CD

Abstract

Inhibition of the mitochondrial Na(+)/Ca(2+) exchanger (NCLX) by CGP37157 is protective in models of neuronal injury that involve disruption of intracellular Ca(2+) homeostasis. However, the Ca(2+) signaling pathways and stores underlying neuroprotection by that inhibitor are not well defined. In the present study, we analyzed how intracellular Ca(2+) levels are modulated by CGP37157 (10 μM) during NMDA insults in primary cultures of rat cortical neurons. We initially assessed the presence of NCLX in mitochondria of cultured neurons by immunolabeling, and subsequently, we analyzed the effects of CGP37157 on neuronal Ca(2+) homeostasis using cameleon-based mitochondrial Ca(2+) and cytosolic Ca(2+) ([Ca(2+)]i) live imaging. We observed that NCLX-driven mitochondrial Ca(2+) exchange occurs in cortical neurons under basal conditions as CGP37157 induced a decrease in [Ca(2)]i concomitant with a Ca(2+) accumulation inside the mitochondria. In turn, CGP37157 also inhibited mitochondrial Ca(2+) efflux after the stimulation of acetylcholine receptors. In contrast, CGP37157 strongly prevented depolarization-induced [Ca(2+)]i increase by blocking voltage-gated Ca(2+) channels (VGCCs), whereas it did not induce depletion of ER Ca(2+) stores. Moreover, mitochondrial Ca(2+) overload was reduced as a consequence of diminished Ca(2+) entry through VGCCs. The decrease in cytosolic and mitochondrial Ca(2+) overload by CGP37157 resulted in a reduction of excitotoxic mitochondrial damage, characterized here by a reduction in mitochondrial membrane depolarization, oxidative stress and calpain activation. In summary, our results provide evidence that during excitotoxicity CGP37157 modulates cytosolic and mitochondrial Ca(2+) dynamics that leads to attenuation of NMDA-induced mitochondrial dysfunction and neuronal cell death by blocking VGCCs.

Authors+Show Affiliations

1] Departamento de Neurociencias, Universidad del País Vasco-UPV/EHU, Barrio Sarriena s/n, Leioa, Spain [2] Achucarro Basque Center for Neuroscience-UPV/EHU, Zamudio, Spain [3] Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, (CIBERNED), Leioa, Spain.1] Departamento de Neurociencias, Universidad del País Vasco-UPV/EHU, Barrio Sarriena s/n, Leioa, Spain [2] Achucarro Basque Center for Neuroscience-UPV/EHU, Zamudio, Spain [3] Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, (CIBERNED), Leioa, Spain.1] Departamento de Neurociencias, Universidad del País Vasco-UPV/EHU, Barrio Sarriena s/n, Leioa, Spain [2] Achucarro Basque Center for Neuroscience-UPV/EHU, Zamudio, Spain [3] Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, (CIBERNED), Leioa, Spain.

Pub Type(s)

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

Language

eng

PubMed ID

24722281

Citation

Ruiz, A, et al. "CGP37157, an Inhibitor of the Mitochondrial Na+/Ca2+ Exchanger, Protects Neurons From Excitotoxicity By Blocking Voltage-gated Ca2+ Channels." Cell Death & Disease, vol. 5, 2014, pp. e1156.
Ruiz A, Alberdi E, Matute C. CGP37157, an inhibitor of the mitochondrial Na+/Ca2+ exchanger, protects neurons from excitotoxicity by blocking voltage-gated Ca2+ channels. Cell Death Dis. 2014;5:e1156.
Ruiz, A., Alberdi, E., & Matute, C. (2014). CGP37157, an inhibitor of the mitochondrial Na+/Ca2+ exchanger, protects neurons from excitotoxicity by blocking voltage-gated Ca2+ channels. Cell Death & Disease, 5, e1156. https://doi.org/10.1038/cddis.2014.134
Ruiz A, Alberdi E, Matute C. CGP37157, an Inhibitor of the Mitochondrial Na+/Ca2+ Exchanger, Protects Neurons From Excitotoxicity By Blocking Voltage-gated Ca2+ Channels. Cell Death Dis. 2014 Apr 10;5:e1156. PubMed PMID: 24722281.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CGP37157, an inhibitor of the mitochondrial Na+/Ca2+ exchanger, protects neurons from excitotoxicity by blocking voltage-gated Ca2+ channels. AU - Ruiz,A, AU - Alberdi,E, AU - Matute,C, Y1 - 2014/04/10/ PY - 2013/11/29/received PY - 2014/02/17/revised PY - 2014/02/27/accepted PY - 2014/4/12/entrez PY - 2014/4/12/pubmed PY - 2015/5/20/medline SP - e1156 EP - e1156 JF - Cell death & disease JO - Cell Death Dis VL - 5 N2 - Inhibition of the mitochondrial Na(+)/Ca(2+) exchanger (NCLX) by CGP37157 is protective in models of neuronal injury that involve disruption of intracellular Ca(2+) homeostasis. However, the Ca(2+) signaling pathways and stores underlying neuroprotection by that inhibitor are not well defined. In the present study, we analyzed how intracellular Ca(2+) levels are modulated by CGP37157 (10 μM) during NMDA insults in primary cultures of rat cortical neurons. We initially assessed the presence of NCLX in mitochondria of cultured neurons by immunolabeling, and subsequently, we analyzed the effects of CGP37157 on neuronal Ca(2+) homeostasis using cameleon-based mitochondrial Ca(2+) and cytosolic Ca(2+) ([Ca(2+)]i) live imaging. We observed that NCLX-driven mitochondrial Ca(2+) exchange occurs in cortical neurons under basal conditions as CGP37157 induced a decrease in [Ca(2)]i concomitant with a Ca(2+) accumulation inside the mitochondria. In turn, CGP37157 also inhibited mitochondrial Ca(2+) efflux after the stimulation of acetylcholine receptors. In contrast, CGP37157 strongly prevented depolarization-induced [Ca(2+)]i increase by blocking voltage-gated Ca(2+) channels (VGCCs), whereas it did not induce depletion of ER Ca(2+) stores. Moreover, mitochondrial Ca(2+) overload was reduced as a consequence of diminished Ca(2+) entry through VGCCs. The decrease in cytosolic and mitochondrial Ca(2+) overload by CGP37157 resulted in a reduction of excitotoxic mitochondrial damage, characterized here by a reduction in mitochondrial membrane depolarization, oxidative stress and calpain activation. In summary, our results provide evidence that during excitotoxicity CGP37157 modulates cytosolic and mitochondrial Ca(2+) dynamics that leads to attenuation of NMDA-induced mitochondrial dysfunction and neuronal cell death by blocking VGCCs. SN - 2041-4889 UR - https://www.unboundmedicine.com/medline/citation/24722281/CGP37157_an_inhibitor_of_the_mitochondrial_Na+/Ca2+_exchanger_protects_neurons_from_excitotoxicity_by_blocking_voltage_gated_Ca2+_channels_ L2 - https://doi.org/10.1038/cddis.2014.134 DB - PRIME DP - Unbound Medicine ER -