INTERLEUKIN-1-BETA INHIBITS CA2-NEURONS THROUGH PROTEIN-KINASE-C( CHANNEL CURRENTS IN HIPPOCAMPAL)

Interleukin-1 beta depresses the voltage-gated Ca2+ channel currents i n acutely dissociated guinea-pig hippocampal CA1 neurons. This depress ion is observed with pathophysiological concentrations found in the ce rebrospinal fluid (greater than or equal to 1.0 pg interleukin-1 beta/ 10 mu l). Interleukin-1 receptor antagonist (in concentrations 25-foId higher than interleukin-1 beta) completely blocked the interleukin-1 beta-induced depression of the Ca2+ channel current. This suggests tha t interleukin-1 beta action is through a specific interaction with an interleukin-1 membrane receptor site. The application of other cytokin es and growth factors (interleukin-6, epidermal growth factor, and bas ic fibroblast growth factor), or bacterial lipopolysaccharide (endotox in) had no effect, indicating specificity of action of interleukin-1 b eta. The depression of the Ca2+ channel current by interleukin-1 beta was prevented by the extracellular application of pertussis toxin, and by the intracellular application of GDP[beta S], H-7, staurosporine o r bisindolylmaleimide. Application of phorbol 12-myristate 13-acetate also depressed the Ca2+ channel current, but this phorbol ester-induce d depression was not additive to that induced by interleukin-1 beta. T hese results suggest mediation of interleukin-1 beta action through a pertussis toxin-sensitive G-protein coupled interleukin-1 receptor ass ociated with the activation of protein kinase C. The depression of the Ca2+ channel current by interleukin-1 beta may be involved in the reg ulation of neuronal excitability during pathological conditions and in the induction and/or progression of neurodegenerative processes.