Essential role of the mitochondrial Na⁺/Ca²⁺ exchanger NCLX in mediating PDE2-dependent neuronal survival and learning.

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 th

SUBMITTER: Rozenfeld M 

PROVIDER: S-EPMC10521900 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature