Accumulation of Inositol Phosphates Induced by Chlorpromazine in C6 Glioma Cells

Abstract

Chlorpromazine, a cationic amphiphilic drug known to affect phospholipid metabolism, greatly increases the generation of inositol phosphates in C6 glioma cells. When a pulse-chase protocol with myo-[2-3H]inositol as the radioactive precursor was used, the peak increase in radioactivity of inositol phosphates was observed at 20 min. The drug decreased inositol tetrakisphosphate labeling as a percentage of inositol trisphosphate in a dose-dependent manner. It also increased the labeling of the inositol-containing phospholipids, the precursors of the inositol phosphates. The increase in radioactivity of both phospholipids and inositol phosphates was dose-dependent, but appeared also to be a function of the time of exposure of the cultures to the drug, suggesting that the concentration of chlorpromazine in the cell, and not that in the medium, is the critical factor. The optimum concentration for maximum phospholipid labeling was lower than that eliciting maximum generation of inositol phosphates. The data suggest that the mechanism probably does not involve cell-surface receptors, but rather may consist of a direct effect of chlorpromazine on phosphoinositidase C and possibly other enzymatic reactions concerned with the metabolism of inositol phosphates.

Protein kinase C isoenzymes in human neuroblasts involvement of PKCε in cell differentiation

“…2). In contrast to a previous observation on another NB cell line [23] we did not find any PKC /I mRNA. This could be ascribed to differences in method evaluation or to a further cell clone-specificity.…”

“…Previous reports have documented changes in PKC during neuronal maturation [22][23][24]331. While these studies have demonstrated modulation of some PKC isoenzymes during treatment of neural cells with PKC inhibitors or they have focused on only few PKC isoforms, they have, however, failed to address whether true differentiation-promoting agents, such as IFN-)I and RA, affect the individual isoforms in a differential manner within the same neuronal model.…”

“…Several proteins which participate in neurofilament reorganization during neural differentiation are themselves substrates for PKC [37]. Moreover, PKCE is nearly exclusively localized in the membranes and processes in NB cells [23]. Thus, it is possible that both the PKCE isoform and particular substrates colocalize during neurite extension and that proximal distribution of the kinase and substrate plays a key role in the acquisition of neuronal phenotype.…”