Inhibition of glia maturation factor-induced mitogenesis in glioblasts by calmodulin antagonists.
The growth inhibitory activity of calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) and trifluoperazine (TFP), was analyzed by the use of rat fetal glioblasts stimulated by glia maturation factor (GMF) or rat astrocytoma cells (C6). The inhibitory effect of W-7 on GMF-induced DNA synthesis of glioblasts was apparent when the drug was added within 10 h after the stimulation by GMF (late G1 phase), but was not shown when W-7 was added at 12 h or later (S phase). The intracellular calmodulin content was built up concurrently with the increase in the DNA synthesis in S phase. The half-maximal inhibition (ID50) of GMF-induced DNA synthesis in glioblasts was observed at 16.5 microM of W-7 or 9.0 microM of TFP. ID50 of DNA synthesis in exponentially growing C6 cells was approximately 3 times higher than that in glioblasts: 24 microM of TFP and as high as 40 microM of W-7. ID50 of growth rate of C6 cells was 15 microM of TFP which was comparable to the ID50 dose for the inhibition of DNA synthesis. Both calmodulin antagonists and W-5, a dechlorinated analog of W-7, however, elicited a curious activation of DNA synthesis of glioblasts at low concentrations (lower than 10 microM of W-7 and W-5, or lower than 5 microM of TFP), indicating non-specific effects of calmodulin antagonists on DNA synthesis. These results suggest that calmodulin antagonists have two conflicting effects on DNA synthesis: the stimulation of DNA synthesis at lower concentrations, and inhibition at higher concentrations.
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002147:Calmodulin / Q000502:physiology*; D002455:Cell Division; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D020904:Glia Maturation Factor; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D009457:Neuroglia / Q000502:physiology*; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014268:Trifluoperazine / Q000494:pharmacology*
D002147:Calmodulin; D020904:Glia Maturation Factor; D009419:Nerve Tissue Proteins; D013449:Sulfonamides; D014268:Trifluoperazine; C017967:W 7; D004247:DNA; D002118:Calcium; D013936:Thymidine