Dynamic change in existing form and physiological significance of calcineurin the brain neuronal cells.

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We used rat brains to elucidate the diversity of the existing forms of calcineurin and its physiolgical significance.1) Calcineurin does not always exist in a heterodimeric form of A and B subunits (1 : 1). A part of calcineeurin could be present as free A and/or B subunits in the brain. We elucidated that the molar ratio of A/B showed a significant difference among various parts of rat brain. Membranc-bound calcineurin was proven to increase in a calcium-dependent manner. In the latter case, B subunit showed much larger change as compared to A,indicating that both subunits could not always make a complex.2) Calcineurin is abundantly present in brain, especially in hippocampus and striatum. In the kindling model rats, the overexpression of calcineurin was observed in hippocampus. When immunosuppressants such cyclosporin A and FK506 were administered to the kindled rats, they could stop the progression of epileptic stages. This inhibition was reversible and the progression of epileptogenesis started after the drugs were stopped. These data indicates that the enhancement of dephosphorylation of various substrates of calcineurin could be involved in the pathogenesis of epilepsy.3) We analyzed the change in intracellular calcium concentration ([Ca]i) in the cultured neurons of rat hippocampus. When the neutralizing antibody was electrophoretically introdued into these neurons, the increase of [Ca] i was larger than that of control neurons. This increase may be attributed to the stimulation of calcium channeling activity of phosphorylated form of calcium channel which is one of the intrinsic substrates of calcineurin.