Essential role of the mitochondrial Na+/Ca2+ exchanger NCLX in mediating PDE2-dependent neuronal survival and learning.
Cell Rep
; 41(10): 111772, 2022 12 06.
Article
en En
| MEDLINE
| ID: mdl-36476859
ABSTRACT
Impaired phosphodiesterase (PDE) function and mitochondrial Ca2+ (i.e., [Ca2+]m) lead to multiple health syndromes by an unknown pathway. Here, we fluorescently monitor robust [Ca2+]m efflux mediated by the mitochondrial Na+/Ca2+ exchanger NCLX in hippocampal neurons sequentially evoked by caffeine and depolarization. Surprisingly, neuronal depolarization-induced Ca2+ transients alone fail to evoke strong [Ca2+]m efflux in wild-type (WT) neurons. However, pre-treatment with the selective PDE2 inhibitor Bay 60-7550 effectively rescues [Ca2+]m efflux similarly to caffeine. Moreover, PDE2 acts by diminishing mitochondrial cAMP, thus promoting NCLX phosphorylation at its PKA site. We find that the protection of neurons against excitotoxic insults, conferred by PDE2 inhibition in WT neurons, is NCLX dependent. Finally, the administration of Bay 60-7550 enhances new object recognition in WT, but not in NCLX knockout (KO), mice. Our results identify a link between PDE and [Ca2+]m signaling that may provide effective therapy for cognitive and ischemic syndromes.
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Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Hidrolasas Diéster Fosfóricas
/
Intercambiador de Sodio-Calcio
Límite:
Animals
Idioma:
En
Revista:
Cell Rep
Año:
2022
Tipo del documento:
Article
País de afiliación:
Israel