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Lysophosphatidic Acid
The structure of lysophosphatidic acid is shown Figure 1. It consists of a long, monounsaturated acyl chain with a polar head including a phosphate group.
Lysophosphatidic acid (LPA) is both a precursor of phospholipid biosynthesis and a signalling phospholipid that is present in nearly all cells, tissues, and fluids of the body [3]. This page will focus on the signalling role of lysophosphatidic acid. LPA is produced from extracellular lysophospholipids by the enzyme autotaxin, and it is derived from membrane glycerophospholipids by phospholipases. LPA interacts with at least six G protein-coupled receptors LPA1-LPA6.
Function
Human lysophosphatidic acid receptor 1 is coupled to a heterotrimeric G protein. The three G alpha proteins that LPA1 couples to are Gi, Gq, and G12/13. The main function of the Gi alpha subunit is the inhibition of the production of cAMP from ATP. cAMP... The Gq alpha subunit activates phospholipase C. The G12/13 subunit regulates cell processes through the use of guanine nucleotide exchange factors.
LPA is part of the larger EDG family which includes the sphingosine 1-phosphate receptors. Compare to S1P...
Targeted deletion of LPA receptors has had an effect on every organ system examined.
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.
