Modulation of protein kinase C and diverse cell functions by sphingosine--a pharmacologically interesting compound linking sphingolipids and signal transduction.

Sphingosine, the backbone moiety of sphingomyelin, gangliosides and other complex sphingolipids, is a potent inhibitor of protein kinase C in vitro and of cellular events dependent on this enzyme. The systems that have been found, thus far, to be affected by sphingosine encompass various components of host defense system, including the activation of platelets, neutrophils and natural killer cells; the cytolytic activity of pathogens and expression of viral genes; cell growth and differentiation in several cell types, including leukemic and neuronal cells; insulin stimulated hexose transport and metabolism in adipocytes; ion-transport systems in various models; the response of neuronal cells to excitatory compounds; and receptor desensitization. While sphingosine has appeared to be a relatively potent and specific inhibitor of protein kinase C in the systems studied, recent findings with the epidermal growth factor receptor indicate that it may serve as a pleotrophic modulator of cell functions. New strategies for the design of pharmacologically active agents should arise from further studies of the action of long-chain (sphingoid) bases. Furthermore, since free sphingosine is a natural constituent of cells and the levels can be modulated by phorbol esters and other factors, a cycle of complex sphingolipid hydrolysis and resynthesis to regulate the amount of free sphingosine may constitute one mechanism of action of these compounds.