Caspase-3 expression by cerebellar granule neurons is regulated by calcium and cyclic AMP

Julio Moran, Takayuki Ito, Usha R. Reddy, Mei Chen, Emad S. Alnemri, David E Pleasure

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

Caspase-3 enzyme activity is induced, and cell death follows, when cerebellar granule neurons (CGNs) from 8-day-old rats are transferred from an extracellular concentration of 25 mM K+ (25 mM [K+](e)) to 5 mM [K+](e). Death of these neurons is diminished by an inhibitor of caspase-3 but not by an inhibitor of caspase-1. Actinomycin D and cycloheximide inhibit induction of caspase-3 and prevent death. Experiments in which CGN intracellular Ca2+ concentration ([Ca2+](i)) was manipulated by either changing [K+](e) or adding a voltage-gated Ca2+ channel antagonist or a Ca2+ ionophore to the medium showed that caspase-3 mRNA rises 2.5-fold when [Ca2+](i) is diminished from 300 to 150 nM, with a corresponding rise in peak caspase enzyme activity. Whereas the caspase-3 mRNA level does not rise further with a still greater diminution in [Ca2+](i), peak caspase enzyme activity continues to increase, reaching sevenfold induction when [Ca2+](i) is reduced to 55 nM. In CGNs in which [Ca2+](i) is set at 55 nM by incubation in 5 mM [K+](e), treatment with forskolin or dibutyryl 3',5'-cyclic adenosine-5'-monophosphate delays caspase-3 induction and diminishes death but does not alter [Ca2+](i). We conclude that, in immature CGNs, both caspase-3 transcription and the subsequent processing of caspase-3 are induced by a fall in [Ca2+](i). Elevating cyclic AMP content delays caspase-3 induction by a mechanism that does not require an increase in [Ca2+](i).

Original languageEnglish (US)
Pages (from-to)568-577
Number of pages10
JournalJournal of Neurochemistry
Volume73
Issue number2
DOIs
StatePublished - 1999
Externally publishedYes

Keywords

  • Apoptosis
  • Caspase-3
  • Cerebellar granule neurons
  • Cyclic AMP
  • Forskolin

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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