A Signaling Role for Phosphatidylserine

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Science's STKE  09 Aug 2005:
Vol. 2005, Issue 296, pp. tw285
DOI: 10.1126/stke.2962005tw285

Exposure of the plasma membrane phosphatidylserine (PS) on the extracellular face of the membrane has been considered a hallmark of an apoptosing cell destined to be removed as debris. Elliott et al. now suggest that, in a subset of T lymphocytes, PS may serve a regulatory role contributing to inflammatory responses and lymphocyte homing. Fluorescent annexin V, which binds to cell surface PS, was used to identify a subset of T cells that also had high amounts of PS on the surface; these cells were CD4+ and also had a low abundance of the transmembrane phosphatase CD45RB. A further connection with CD45RB was noted when cells were sorted by flow cytometry after stimulation of the ATP receptor P2X7, which revealed that only cells with low CD45RB responded to P2X7 activation with exposure of PS on the cell surface. Pharmacological inhibition of PS redistribution prevented proteolytic release of the homing receptor CD62L (CD62L shedding) in response to P2X7 activation. Using the C6 T cell clone, the authors showed that exposure of the cells to annexin V inhibited cell migration in vitro and in vivo, which suggests that cell surface PS may have a role in lymphocyte infiltration. Calcium and sodium uptake in response to P2X7 activation was blocked in the presence of inhibitors of the PS translocation enzymes. Thus, the authors propose that P2X7 stimulation triggers PS flipping, which is required for opening of the P2X7 channel, and that PS on the intracellular face of the membrane inhibits the channel activity of P2X7. Flipping of PS to the cell surface also correlated with P2X7-mediated inhibition of the multidrug transporter P-glycoprotein, and this effect was blocked by pharmacological inhibition of the PS translocation enzymes. Thus, PS appears to be another lipid in the membrane that can alter membrane protein activity and, in this case, the regulatory mechanism involves the repositioning of the lipid in the intra- or extracellular face of the membrane.

J. I. Elliott, A. Surprenant, F. M. Marelli-Berg, J. C. Cooper, R. L. Cassady-Cain, C. Wooding, K. Linton, D. R. Alexander, C. F. Higgins, Membrane phosphatidylserine distribution as a non-apoptotic signalling mechanism in lymphocytes. Nat. Cell. Biol. 7, 808-816 (2005). [PubMed]

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