Differential localization of sphingomyelin synthase isoforms in neurons regulates sphingomyelin cluster formation

Sphingomyelin (SM) plays important roles in regulating structure and function of plasma membrane, but how intracellular localization of SM is regulated in neuronal cells is not understood. Here we show that two isoforms of SM synthase (SMS) are differentially expressed in neuronal subtypes and that only SMS2 proteins localize in neurites of hippocampal neurons. Moreover, SMS proteins induce Lysenin-binding SM clusters exclusively in their vicinity although neurons hardly contain such cluster under control condition. These findings indicate three important notions about SM metabolism in neurons. First, the activity of SMS is the rate-limiting step of SM cluster formation. Second, the SM content or clustering can be modulated by SMS activity. Third, SMS1 and SMS2 play distinct roles in regulating local SM clustering. Particularly, SMS2, rather than SMS1, is likely to be the major enzyme that is important for SM synthesis in the long neurites and its tip, the growth cone.