Loss of type II calcium/calmodulin-dependent kinase activity correlates with stages of development of electrographic seizures in status epilepticus in rat.
Understanding the molecular basis of altered neuronal excitability in epilepsy is a major challenge in neuroscience research. The present study suggests an inverse correlation between changes in neuronal excitability in status epilepticus and the activity of type II multifunctional calcium/calmodulin-dependent kinase II (CaM kinase II), a major Ca(2+)-signal transducing system in brain. 'Continuous' hippocampal stimulation (CHS), a new model of non-convulsive limbic status epilepticus (SE), mimics the progression of electrographic changes characteristic in human SE and allows for quantitation of post-stimulus seizure severity. In the present study, hippocampus and anterior neocortex from CHS-stimulated rats and paired surgical controls were assayed for CaM kinase II activity by incorporation of radiolabeled phosphate from [gamma-32P]ATP into the 50-kDa subunit of the kinase itself (autophosphorylation). In all instances, CHS induced sustained interictal bursting and/or electrographic seizures. Decreased CaM kinase II activity was seen in all preparations from electrically stimulated hippocampus. CaM kinase II activity in CHS animals was diminished by 37% relative to controls (P less than 0.01; Student's paired t-test). The progressive intensity of the EEG discharges correlated directly with the decrement of CaM kinase II activity (P less than 0.05; Spearman's rank correlation test, n = 5). This is the first report of a dynamic modulation of a biochemical system that has been implicated in neuronal excitability in coordination with the characterized developmental stages of SE.
Perlin
J B
JB
Department of Neurology, Medical College of Virginia, Richmond 23298.
Churn
S B
SB
Lothman
E W
EW
DeLorenzo
R J
RJ
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002540:Cerebral Cortex / Q000201:enzymology; D004558:Electric Stimulation; D004569:Electroencephalography; D004591:Electrophoresis, Polyacrylamide Gel; D006624:Hippocampus / Q000201:enzymology / Q000502:physiology; D008297:Male; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000201:enzymology*; D013226:Status Epilepticus / Q000201:enzymology / Q000503:physiopathology*
D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases