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Lysophosphatidic Acid

Lysophosphatidic Acid (LPA) consists of an unsaturated fatty acid chain, a glycerol backbone, and a free phosphate group (Figure 1). Its chemical name is monoacyl-sn-glycero-3-phosphate. Lysophosphatidic acid is found in nearly all cells, tissues, and fluids of the body. LPA is present intracellularly as a precursor of phospholipid biosynthesis, and extracellularly as a signalling phospholipid. This page will focus on the signalling role of LPA.

Extracellularly, LPA is produced from lysophosphatidylcholine by the enzyme autotaxin. All of LPA’s activities are receptor mediated; the signalling lipid interacts with at least six G-protein coupled receptors LPA₁-LPA₆.

Function

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Of the six LPA G-protein coupled receptors, LPA₁ is the most widely expressed. Lysophosphatidic acid receptor 1 is coupled to a heterotrimeric G protein. The three G alpha proteins that LPA₁ couples to are G_i, G_q, and G_12/13. From these three G proteins many signal transduction pathways are activated. The downstream effects of G_i are cell proliferation, cell survival, cell migration, and morphological changes. G_q signals the inhibition of gap-junctional communication. Those of G_12/13 are morphological changes, inhibition / reversal of differentiation, contraction, and increased endothelial permeability. These downstream functions show the wide array of effects that LPA can have on the body. Targeted deletion of LPA receptors has had an effect on every organ system examined.

LPA₁ is part of the larger EDG (endothelial differentiation gene) family which includes the sphingosine 1-phosphate receptors. Compare to S1P…

Structure

The LPA1 receptor consists of seven transmembrane alpha helices. There are more (red) resides on the intercellular and extracellular areas of the receptor, while most residues positioned inside the membrane are hydrophobic (blue).

There are many different stabilizing factors in the structure of this receptor. There are three native disulfide bonds in the extracellular region. One of these bonds constrains the N terminal helix to extracellular loop 2. The functions like a cap on the extracellular side of the protein, packing tightly against ECL1 and ECL2. It also provides that interact with the ligand when bound.

The for LPA inside the receptor consists of both polar and nonpolar residues. There are polar residues on the N terminus and along one side of the binding pocket. There is also a large hydrophobic pocket for the long acyl chain of LPA.

Similarities to S1P

Clinical Relevance

Infertility

Fibrosis

Cancer

Endocannabinoids

The endocannabinoid system, located in the mammalian nervous system, regulates a variety of physiological processes including appetite, pain sensation, mood, and memory. Endocannabinoids, the natural ligands for cannabinoid receptors, are similar in structure to lysophosphatidic acid. Both the cannabinoid receptors and the LPA receptors have a preference for long unsaturated acyl chains.