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- W3182735127 abstract "Abstract Impaired phosphodiesterase (PDE) function and mitochondrial Ca 2+ - [Ca 2+ ]m signaling leads to cardiac failure, ischemic damage and dysfunctional learning and memory. Yet, a causative link between these pathways is unknown. Here, we fluorescently monitored [Ca 2+ ]m transients in hippocampal neurons evoked by caffeine followed by depolarization. [Ca 2+ ]m efflux was apparent in WT but diminished in neurons deficient in the mitochondrial Na + /Ca 2+ exchanger NCLX. Surprisingly, neuronal depolarization-induced Ca 2+ transients alone failed to evoke strong [Ca 2+ ]m efflux in WT neurons. Caffeine is also a PDE inhibitor. Pretreatment with the PDE2 inhibitor Bay 60-7550 rescued [Ca 2+ ]m efflux triggered by neuronal depolarization. Inhibition of PDE2 acted by diminishing the Ca 2+ dependent reduction of mitochondrial cAMP, thereby promoting NCLX phosphorylation. Selective PDE2 inhibition also enhanced [Ca 2+ ]m efflux triggered by neuromodulators. We found that protection of neurons against excitotoxic insults, conferred by PDE2 inhibition, was diminished in NCLX KO neurons, thus is NCLX dependent. Finally, administration of Bay 60-7550 enhanced new object recognition learning in WT but not in NCLX KO mice. Our results identify a long-sought link between PDE and [Ca 2+ ]m signaling thereby providing new therapeutic targets." @default.
- W3182735127 created "2021-07-19" @default.
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- W3182735127 date "2021-07-09" @default.
- W3182735127 modified "2023-09-23" @default.
- W3182735127 title "The mitochondrial Na+/Ca2+ exchanger, NCLX, mediates PDE2 dependent neuronal survival and learning" @default.
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- W3182735127 doi "https://doi.org/10.1101/2021.07.08.451717" @default.
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