N-methyl-D-aspartate receptor dependent transcriptional regulation of two calcium/calmodulin-dependent protein kinase type II isoforms in rodent cerebral cortex.

ABSTRACT

Alpha Calcium/calmodulin-dependent protein kinase type II (CaMKII-alpha) expression is regulated in an activity-dependent manner, but it is not known whether other CaMKII isoforms (beta, delta, and gamma) are similarly regulated. We examined the activity-dependent regulation of these CaMKII isoforms in vivo, using a model of generalized seizures caused by i.p. injection of kainic acid. Following seizure induction, CaMKII-alpha expression was downregulated and CaMKII-delta expression upregulated while CaMKII-beta and CaMKII-gamma expression was unaffected. A transient downregulation in CaMKII-alpha and a transient increase in CaMKII-delta occurred throughout neocortex in the same temporal order. Although CaMKII-alpha mRNA was decreased by seizure activity, the less abundant, alternatively spliced, CaMKII-alpha33 mRNA was unaffected. Organotypic cortical slice cultures treated with bicuculline and 4-aminopyridine to induce seizure activity also showed a downregulation of CaMKII-alpha mRNA and an upregulation of CaMKII-delta mRNA. Prior exposure to tetrodotoxin prevented the changes in CaMKII-alpha and CaMKII-delta mRNA regulation and this was mimicked by D-L-2-amino-5-phosphonovaleric acid, but not by 6-cyano-2,3-dihydroxy-7-nitro-quinoxaline, suggesting that CaMKII-alpha and CaMKII-delta mRNA expression is regulated in an N-methyl-D-aspartate receptor-dependent manner. Regulation was also transcription dependent. Blocking transcription with actinomycin-D prevented activity-dependent changes in CaMKII-alpha and CaMKII-delta mRNA, but produced opposite effects on basal transcription, resulting in more stabilized CaMKII-alpha mRNA and less stabilized CaMKII-delta mRNA. These results reveal unique patterns of seizure-induced alterations in CaMKII mRNAs. Activity-dependent changes in subunit composition could, therefore, differentially influence the functional attributes of the CaMKII holoenzyme.