Regulation of phospholipase Cδ activity by sphingomyelin and sphingosine

Abstract

Phospholipase Cδ (PLCδ) is strongly inhibited by sphingomyelin (SM). The inhibition occurs in both the presence and the absence of spermine, an activator of PLCδ. Phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylinositol (PI) also inhibit PLCδ in the presence of spermine but are much less effective than SM. PE and PC activate and PS and PI inhibit PLCδ in the absence of spermine. Again, the inhibition by PS and PI is much weaker than the inhibition observed with SM. Similar or identical effects are observed in detergent micelle and liposome assays. Comparisons of physiological concentrations of SM with concentrations yielding 50% inhibition of PLCδ in vitro indicate that SM is likely to be a major factor in regulating the activity of PLCδ by inhibition. It is proposed that, in vivo, sphingomyelin acts as an inhibitor of PLCδ, which enables the enzyme to be regulated by activation. In certain circumstances, there is a substantial decline in SM and this may lead to a partial relief of the inhibition. PLCδ is activated by sphingosine in the absence of spermine. However, this activation occurs at unphysiologically high concentrations of sphingosine. The effects of SM and sphingosine on PLCδ are in marked contrast to those observed with protein kinase C, which is unaffected by sphingomyelin and inhibited by sphingosine (Hannun, Y. A. and Bell, R. M., 1989, Science 243, 500–507).