PROTEIN-KINASE-C DOWN-REGULATION IN ASTROCYTES - DIFFERENTIAL-EFFECTSON AGONIST-STIMULATED INOSITOL PHOSPHATE ACCUMULATION

Prolonged phorbol ester treatment abolished protein kinase C (PKC) act ivity for over 48 h in cortical astrocyte cultures. Receptor-stimulate d inositol phospholipid breakdown in these cultures subsequent to PKC depletion produced either enhanced, depressed or unchanged responses d epending upon the agonist used. Noradrenaline-, ATP-, histamine- and g lutamate-evoked [H-3]-inositol phosphate accumulations were potentiate d to varying degrees in PKC-depleted cultures whilst those evoked by c arbachol and NaF were reduced and unchanged respectively. Analysis of the individual metabolites of inositol phospholipid metabolism formed in response to noradrenaline in PKC-depleted astrocytes revealed poten tiated accumulations of radiolabelled glycerophosphoinositol (GPI), in ositol monophosphate (IP1) and inositol bisphosphate (IP2) but not ino sitol trisphosphate (IP3) when compared to controls. Under the same co nditions, accumulations of radiolabelled IP1 and IP2 were reduced and those of GPI and IP3 unchanged in carbachol-treated cultures. These re sults suggest that astrocyte receptors coupled to inositol phospholipi d metabolism are differentially regulated by PKC.