LPA-Membrane interaction: Probing the signaling mechanism of Lysophosphatidic Acid

Abstract

Lysophosphatidic acid (LPA) is the simplest naturally occurring phospholipid composed of only a single acyl chain and phosphate head group esterified to a glycerol backbone. LPA is found intracellularly as a vital precursor for complex lipid synthesis, but more importantly, it functions as a bioactive, extracellular signalling molecule through a membrane-bound G-protein coupled receptor. Yet, because LPA is amphipathic and is present in high concentrations within the mammalian bloodstream, it is possible that LPA also directly acts at the membrane level. We suggest here that LPA-membrane interaction does occur and may be important for regulating its cell signalling capabilities through the reassembling and modification of membrane lipid organization. Using qualitative phospholipid/cholesterol MLV solubilization experiments, we have found that LPA interacts with fluid-phase vesicles by increasing their turbidity whereas LPA tends to solubilize more ordered, gel-phase vesicles. In addition, it appears that LPA has a much stronger affinity for and association with DPPC than with either DOPC or POPC. These findings suggest that LPA may modify the binding and activity of its target receptor in a regulatory fashion by altering the surrounding membrane environment. Fluorescent dye leakage studies are being conducted and adjusted to test the ability of LPA to perforate the membrane.