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From Proteopedia

Human Lysophosphatodic Acid Receptor 1

Lysophosphatodic Acid

Figure 1: Chemical Structure of LPA

Function

LPA, a signaling phospholipid, can attach to three specific G-protein-coupled receptors. LPA can activate multiple pathways in particular, Ras and Pho which belong to the family of GTPases. Another use of LPA is it can help in stimulation of cell migration ^[1].

Structure

LPA Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Comparison of S1P and LPA Lysophosphatidic Acid Receptors (LPA) are part of a larger family known as lysophospholipid receptor family (EDG family). Within this family there is a structure called S1P1. Since only the structures for LPA1 and S1P1 are known in the EDG family, comparisons are made between the two structures [2]. There is a difference in binding paths between these two receptors. The binding path in the LPA1 is located in the extracellular milieu. While in the S1P1 the ligands are able to have access to the membrane so that the binding can occur. Figure 2: Comparison of the binding pockets of LPA1 and S1P1 receptors There is a difference in the shape of the electron density from the binding pocket. In S1P1 the binding pocket has more of an oval shape. For the LPA1 receptor the binding pocket has a spherical shape. Since the binding pocket is more spherical it gives LPA1 the ability to be able to recognize a larger group of chemical species. In particular the ability to bind with acyl chains of varying lengths [2]. Function Relevance

Clinical Testing

LPA is still in the clinical stage of testing. So far the LPA receptors have had physiological effects on every organism that it has been tested with. There have been studies done looking at what happens with infertility, fibrosis, pain, and cancer when they come into contact with LPA receptors ^[2]. LPA receptors are commonly found in serum and saliva. ^[1].

Pain

LPA, a signaling phospholipid, that attaches to three specific G-protein-coupled receptors. After an injury occurs LPA is released in the body. It then will activate G-protein-coupled receptors. Within the nervous system, LPA plays a role in the nociceptive process (nociceptive pain is a sharp pain that can come from a mild burn or twisted ankle). The LPA signaling will activate GTPase RhoA. Once activated Rho translocates to the plasma membrane. Rho will activate Rho kinase (ROCK). Mice with the deletation of LPA₁ receptors were studied to see the role that LPA signaling played in pain. In a study done with mice, those without the LPA₁ receptor had lower levels of pain.^[3]. Another use of LPA is it can help in stimulation of cell migration ^[1].

Fibrosis

To better understand the role the LPA plays in fibrosis, a study was done with mice who had contracted fibrosis ^[4]. Idiopathic pulmonary fibrosis (IPF) has high rates of mortality. Research has been done to study the pathway of the LPA-LPA₁ in fibroblast migration ([1]). The bronchoalveolar lavage (BAL) in mice that had fibrosis was elevated. The research supported the hypothesis that LPA₁ plays an active role between lung injury and contracting pulmonary fibrosis.

References

1. ↑ ^{1.0 1.1 1.2} Moolenaar WH, van Meeteren LA, Giepmans BN. The ins and outs of lysophosphatidic acid signaling. Bioessays. 2004 Aug;26(8):870-81. PMID:15273989 doi:http://dx.doi.org/10.1002/bies.20081
2. ↑ ^{2.0 2.1 2.2} Chrencik JE, Roth CB, Terakado M, Kurata H, Omi R, Kihara Y, Warshaviak D, Nakade S, Asmar-Rovira G, Mileni M, Mizuno H, Griffith MT, Rodgers C, Han GW, Velasquez J, Chun J, Stevens RC, Hanson MA. Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1. Cell. 2015 Jun 18;161(7):1633-43. doi: 10.1016/j.cell.2015.06.002. PMID:26091040 doi:http://dx.doi.org/10.1016/j.cell.2015.06.002
3. ↑ Inoue M, Rashid MH, Fujita R, Contos JJ, Chun J, Ueda H. Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling. Nat Med. 2004 Jul;10(7):712-8. Epub 2004 Jun 13. PMID:15195086 doi:http://dx.doi.org/10.1038/nm1060
4. ↑ Tager AM, LaCamera P, Shea BS, Campanella GS, Selman M, Zhao Z, Polosukhin V, Wain J, Karimi-Shah BA, Kim ND, Hart WK, Pardo A, Blackwell TS, Xu Y, Chun J, Luster AD. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat Med. 2008 Jan;14(1):45-54. Epub 2007 Dec 9. PMID:18066075 doi:http://dx.doi.org/10.1038/nm1685