Previously we showed that
hypoxia results in increased neuronal nuclear Ca(2+) influx,
Ca(2+)/calmodulin-dependent protein kinase IV activity (CaM KIV) and phosphorylation of c-
AMP response element binding (
CREB) protein. The aim of the present study was to understand the importance of neuronal nuclear Ca(2+) in the role of CaM KIV activation and
CREB protein phosphorylation associated with
hypoxia. To accomplish this the present study tests the hypothesis that
clonidine administration will block increased nuclear Ca(2+) influx by inhibiting high affinity Ca(2+)/
ATPase and prevent increased CaM KIV activity and CREB phosphorylation in the neuronal nuclei of the cerebral cortex of hypoxic newborn piglets. To accomplish this piglets were divided in three groups: normoxic, hypoxic, and hypoxic-treated with
clonidine. The piglets that were in the Hx+Cl group received
clonidine 5 min prior to
hypoxia. Cerebral tissue
hypoxia was confirmed biochemically by tissue levels of
ATP and
phosphocreatine (PCr). The data show that
clonidine prevents
hypoxia-induced increase in CaM KIV activity and
CREB protein phosphorylation. We conclude that the mechanism of
hypoxia-induced activation of CaM KIV and CREB phosphorylation is nuclear Ca(2+) influx mediated. We speculate that nuclear Ca(2+) influx is a key step that triggers CREB mediated transcription of apoptotic
proteins and hypoxic mediated neuronal death.