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Caspase‐3 Expression by Cerebellar Granule Neurons Is Regulated by Calcium and Cyclic AMP
Author(s) -
Moran Julio,
Itoh Takayuki,
Reddy Usha R.,
Chen Mei,
Alnemri Emad S.,
Pleasure David
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0730568.x
Subject(s) - forskolin , cycloheximide , extracellular , microbiology and biotechnology , intracellular , activator (genetics) , biology , calcium , cerebellum , medicine , chemistry , endocrinology , biochemistry , stimulation , protein biosynthesis , receptor
: 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 m M K + (25 m M [K + ] e ) to 5 m M [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 Ca 2+ concentration ([Ca 2+ ] i ) was manipulated by either changing [K + ] e or adding a voltage‐gated Ca 2+ channel antagonist or a Ca 2+ ionophore to the medium showed that caspase‐3 mRNA rises 2.5‐fold when [Ca 2+ ] i is diminished from 300 to 150 n M , 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 [Ca 2+ ] i , peak caspase enzyme activity continues to increase, reaching sevenfold induction when [Ca 2+ ] i is reduced to 55 n M . In CGNs in which [Ca 2+ ] i is set at 55 n M by incubation in 5 m M [K + ] e , treatment with forskolin or dibutyryl 3′,5′‐cyclic adenosine‐5′‐monophosphate delays caspase‐3 induction and diminishes death but does not alter [Ca 2+ ] i . We conclude that, in immature CGNs, both caspase‐3 transcription and the subsequent processing of caspase‐3 are induced by a fall in [Ca 2+ ] i . Elevating cyclic AMP content delays caspase‐3 induction by a mechanism that does not require an increase in [Ca 2+ ] i .