Sphingomyelinases and the Regulation of Cell Death and Survival

The breakdown of sphingomyelin by sphingomyelinases (SMases) is a crucial event in the regulation of cell survival. This action produces ceramide, which acts as a second messenger to stimulate or inhibit downstream effectors leading to cell growth arrest, or apoptosis. Mammalian cells utilize three distinct forms of SMases, which can be distinguished by their optimum pH: acidic, neutral, or alkaline SMases. Acidic and neutral SMases are particularly important because they are involved in signal transduction processes. However, stimulation of SMase activity is not necessarily a pro-apoptotic event, as ceramides are subject to rapid metabolism by intracellular ceramidases and kinases to form sphingosine, sphingosine-1-phosphate, or ceramide-1-phosphate, all of which have mitogenic, or cytoprotective properties. Therefore, the balance of the intracellular levels of pro-apoptotic ceramides and anti-apoptotic (or mitogenic) sphingosine-1-phosphate and ceramide-1-phosphate is crucial for determining the overall signal that is finally transmitted in cells. A better understanding of the interactions between the different metabolites that can be generated from the SMase pathway would be relevant for elucidation of the mechanisms that regulate cellular functions, in particular cell death and proliferation. Most importantly, the development of inhibitors of SMases may be crucial for establishing therapeutic strategies for treatment of disease.