Research: Phosphoinositides/Phospholipids

Phosphoinositides

Visualizing Phospholipid (PL) and Phosphoinositide (PtdInsPn) and Signaling in Cells.

Cell signaling via lipids such as phosphoinositides (PIPs) and lysophosphatidic acid (LPA) are accomplished by ligand activation of GPCRs, ligand-mediated protein recruitment, and protein-catalyzed lipid remodeling by phospholipases, phosphatases, and kinases. This talk with cover novel probes for cell biology based on chemically-synthesized PIP and LPA analogs. First, for the PIPs, two novel chemical architectures, polymerized PIP-containing liposomes and two-headed hybrid PIP-phospholipids, offer significant advantages for interrogation of cellular lipid signaling. We describe the preparation and uses of metabolically-stabilized PIPs, in which phosphonates and other functionalities are selectively introduced to resist kinase, phosphatase, and phospholipase cleavage. Second, for LPA, we have developed synthetic routes for the preparation of long-lived receptor-specific agonists and antagonists that are selective for LPA GPCRs isoforms. Other ligands act as inhibitors of lysoPLD and lipid phosphate phosphatase (LPP). Furthermore, fluorogenic substrates to provide real-time data on head-group selective phospholipase A and D activities in cells have been developed. Examples of the use of specific new probes in biological systems will be presented.

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