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 language | English (US) |
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Pages (from-to) | 568-577 |
Number of pages | 10 |
Journal | Journal of Neurochemistry |
Volume | 73 |
Issue number | 2 |
DOIs | |
State | Published - 1999 |
Externally published | Yes |
Keywords
- Apoptosis
- Caspase-3
- Cerebellar granule neurons
- Cyclic AMP
- Forskolin
ASJC Scopus subject areas
- Biochemistry
- Cellular and Molecular Neuroscience