Inhibition of CRAC through Sphingolipids

Science's STKE  01 Dec 1999:
Vol. 1999, Issue 10, pp. tw5
DOI: 10.1126/stke.1999.10.tw5

The receptor CD95 (also called Fas or Apo-1) inhibits T cell activation. Activation of CD95 can cause apoptosis in lymphocytes and may have other effects as well. Lepple-Wienhues et al. show that activation of CD95 inhibits calcium influx through calcium release--activated calcium channels (CRAC). Their results indicate that stimulation of CD95 activates acidic sphingomyelinase and causes consequent release of ceramide. Ceramide appears to inhibit influx of calcium that would normally accompany depletion of intracellular calcium stores. As a result, calcium-dependent signals from the T cell receptor are inhibited, as are their biological effects such as synthesis of interleukin-2. Members of the nerve growth factor or tumor necrosis factor family also can activate acidic sphingomyelinase and inhibit CRAC. Thus, the authors propose that such sphingolipid-mediated signals could be a widely used mechanism to inhibit calcium-dependent signals in lymphocytes.

Lepple-Wienhues, A., Belka, C., Laun, T., Jekle, A., Walter, B., Wieland, U., Welz, M., Heil, L., Kun, J., Busch, G., Weller, M., Banberg, M., Gulbins, E., and Lang, F. (1999) Stimulation of CD95 (Fas) blocks T lymphocyte calcium channels through sphingomyelinase and sphingolipids. Proc. Natl. Acad. Sci. U.S.A. 96: 13795-13800. [Abstract] [Full Text]