Ceramide, generated by the action of acid sphingomyelinase (ASM), has emerged as a biochemical mediator of stimuli as diverse as ionizing radiation, chemotherapy, UVA light, heat, CD95, reperfusion injury, as well as infection with some pathogenic bacteria and viruses. ASM activity is also crucial for developmental programmed cell death of oocytes by apoptosis. Recently, we proposed a comprehensive model that might explain these diverse functions of ceramide: Upon contacting the relevant stimuli, ASM translocates into and generates ceramide within distinct plasma membrane sphingolipid-enriched microdomains termed rafts. Ceramide, which manifests a unique biophysical property, the capability to self-associate through hydrogen bonding, provides the driving force that results in the coalescence of microscopic rafts into large-membrane macrodomains. These structures serve as platforms for protein concentration and oligomerization, transmitting signals across the plasma membrane. Preliminary data suggest that manipulation of ceramide metabolism and/or the function of ceramide-enriched membrane platforms may present novel therapeutic opportunities for the treatment of cancer, degenerative disorders, pathogenic infections or cardiovascular diseases.
