title: Mechanism of Ca(2+)/calmodulin-dependent protein kinase IV activation and of cyclic AMP response element binding protein phosphorylation during hypoxia in the cerebral cortex of newborn piglets.
abstract: 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.
authors.affiliation: Drexel University College of Medicine Division of Neonatology Department of Pediatrics Mail Stop 1029 245 N, 15th Street Philadelphia, PA 19102, USA. khornickdo@hotmail.com
authors.forename: Kristie
authors.initials: K
authors.lastname: Hornick
authors.forename: Eddie
authors.initials: E
authors.lastname: Chang
authors.forename: Alan B
authors.initials: AB
authors.lastname: Zubrow
authors.forename: Om P
authors.initials: OP
authors.lastname: Mishra
authors.forename: Maria
authors.initials: M
authors.lastname: Delivoria-Papadopoulos
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage; D000818:Animals; D000831:Animals, Newborn; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003000:Clonidine / Q000008:administration & dosage; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000648:ultrastructure; D010725:Phosphocreatine / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D013552:Swine
chemical_list: D000316:Adrenergic alpha-Agonists; D017362:Cyclic AMP Response Element-Binding Protein; D010725:Phosphocreatine; D000255:Adenosine Triphosphate; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C088320:calmodulin-dependent protein kinase V; D003000:Clonidine