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Functional proteins involved in regulation of intracellular Ca(2+) for drug development: role of calcium/calmodulin-dependent protein kinases in ischemic neuronal death.
- Source :
-
Journal of pharmacological sciences [J Pharmacol Sci] 2005 Mar; Vol. 97 (3), pp. 351-4. Date of Electronic Publication: 2005 Mar 12. - Publication Year :
- 2005
-
Abstract
- Excessive elevation of intracellular calcium level seems to be a trigger of ischemic neuronal injury. Calcium/calmodulin (CaM)-dependent protein kinase kinase (CaM-KK) is an upstream kinase for CaM kinase IV (CaM-KIV) that was reported to prevent apoptosis through phosphorylation of CREB (cyclic AMP responsive element-binding protein). We here observed that CaM-KK could directly activate Akt, thereby preventing apoptosis in cultured cells. Then we examined changes in Akt and CaM-KIV activities in gerbil forebrain ischemia. In 5-min-ischemia-caused delayed neuronal death in hippocampal CA1 neurons, Akt and CaM-KIV activities were decreased after reperfusion. On the other hand, during induction of ischemic tolerance, Akt activity gradually and persistently increased in the CA1 neurons with transient increase in CREB phosphorylation. Inhibition of Akt activity with wortmannin or CREB-DNA binding with CRE-decoy injection resulted in failure of generation of ischemic tolerance. These results indicated activation of Akt and CaM-KIV play important roles in induction of the ischemic tolerance. Activation of CaM-KK may provide a new strategy for overcoming the ischemic stress.
- Subjects :
- Androstadienes pharmacology
Animals
Brain Ischemia metabolism
Calcium-Calmodulin-Dependent Protein Kinase Kinase
Calcium-Calmodulin-Dependent Protein Kinase Type 4
Calcium-Calmodulin-Dependent Protein Kinases metabolism
Cell Line
Cyclic AMP Response Element-Binding Protein metabolism
Enzyme Activation drug effects
Gerbillinae
Hippocampus cytology
Models, Biological
Neurons metabolism
Phosphorylation
Protein Serine-Threonine Kinases metabolism
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-akt
Wortmannin
Apoptosis drug effects
Calcium metabolism
Drug Design
Ischemic Preconditioning
Neurons cytology
Subjects
Details
- Language :
- English
- ISSN :
- 1347-8613
- Volume :
- 97
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of pharmacological sciences
- Publication Type :
- Academic Journal
- Accession number :
- 15764842
- Full Text :
- https://doi.org/10.1254/jphs.fmj04007x5