{{Sandbox_Reserved_CH462_Central_Metabolism}}
==Human Lysophosphatidic Acid Receptor 1==

== Lysophosphatidic Acid ==

[[Image:LPA.png|220px|left|thumb|'''Figure 1:''' Chemical Structure of LPA (monoacyl-sn-glycero-3-phosphate)]]

Lysophosphatidic Acid (LPA) consists of an unsaturated fatty acid chain, a glycerol backbone, and a free phosphate group (Figure 1). Lysophosphatidic acid is found in nearly all cells, tissues, and fluids of the body.<ref name= "Chrencik"> DOI: 10.1016/j.cell.2015.06.002 </ref> LPA is present intracellularly as a precursor of phospholipid biosynthesis, and extracellularly as a signalling phospholipid.

Extracellularly, LPA is produced from lysophosphatidylcholine by the enzyme autotaxin.<ref name= "Chrencik"/> Autotaxin was originally linked with metastasis, and this link was later discovered to be mediated through the production of LPA, which signals cell proliferation.<ref name= "Boutin"> DOI: 10.1007/s00018-009-0056-9 </ref> All of LPA’s activities are receptor mediated; the signalling lipid interacts with at least six G-protein coupled receptors LPA1-LPA6.

== Structure ==
<StructureSection load='4z34' size='340' side='right' caption=' LPA Receptor 1 ' scene='72/721545/Overall/1'>
The LPA1 receptor consists of seven transmembrane alpha helices. It lies in the membrane as shown in Figure 2, and as shown by the <scene name='72/721545/Membrane/4'>fatty acid</scene> bound in the crystallization of LPA1 in orange. Most <scene name='72/721545/Polarity/3'>polar</scene> (red) reside on the intracellular and extracellular areas of the receptor, while most residues positioned on the trans membrane helices inside the membrane are hydrophobic (blue). A cytochrome b (b562RIL) protein was inserted into the third intracellular loop to facilitate crystallization (Figure 2).

[[Image:LPA_in_membrane4.fw.png|200px|center|thumb|'''Figure 2:''' LPA receptor (blue) bound to the cell membrane. The binding pocket is highlighted in red. The added bRIL protein is shown in orange.]]

=== Structural Stabilization ===

Three native <scene name='72/721545/Disulfides/2'>disulfide bonds</scene> in the extracellular region of this receptor provide fold stability.<ref name= "Chrencik"/> The first disulfide bond constrains the N terminal helix to extracellular loop(ECL) 2. The second disulfide bond shapes ECL2, and the third binds ECL3 to one of the transmembrane alpha helices. The <scene name='72/721545/N-terminus/2'>N-terminus</scene> functions like a cap on the extracellular side of the protein, packing tightly against ECL1 and ECL2. The N-terminus alpha helix also provides <scene name='72/721545/34_39_40/3'>polar amino acids</scene> that interact with the ligand when bound.

=== Binding Pocket ===

The ligand shown in this structure, ONO-9780307, has a similar structure to LPA, and was bound to LPA1 for crystallization to visualize the binding pocket. <ref name= "Moolenaar" /> The <scene name='72/721545/Ligand/2'>binding pocket</scene> for LPA consists of both polar and nonpolar residues. <scene name='72/721545/All_polar_interactions/5'>Polar</scene> residues are located on the N terminus and within the binding pocket (<scene name='72/721545/All_polar_interactions/6'>polar residues</scene>). There is also a <scene name='72/721545/Hydrophobic_pocket/3'>hydrophobic pocket</scene> that interacts with the long acyl chain of LPA.

=== Sphingosine-1-Phosphate Receptor ===

Lysophosphatidic Acid Receptors (LPA) are part of a larger family known as lysophospholipid receptor family (EDG family), including the archetype sphingosine-1-phosphate receptors (S1P1). The only structure previously reported in this GPCR family was of S1P1, and it provides a comparison for differential structure and function to LPA1. <ref name= "Chrencik"/> A major difference was observed in ligand access between these two receptors. The binding path in LPA1 is located in the extracellular milieu, while in S1P1 the ligand accesses the binding pocket through the membrane (Figure 3). The overall shape of each binding pocket is also different, as the S1P1 binding pocket has more of an oval shape, whereas [[Image:LPA S1P.png|300px|left|thumb|'''Figure 3:''' Comparison of the binding pockets of LPA1 and S1P1 receptors. The electron density (tan) of the binding pocket is shown around the ligand (purple). The limited binding sites of the receptors are shown in tan.]] the LPA1 binding pocket has a more spherical shape (Figure 3). The more spherical binding pocket for LPA1 gives it the ability to recognize a larger group of chemical species. In particular, LPA1 has the ability to bind with ligands that have acyl chains of varying lengths <ref name= "Chrencik"/>. Since LPA1 binds with a variety of acyl chains, it can be used in multiple pathways.

</StructureSection>

== Function ==

Of the six LPA G-protein coupled receptors, Lysophosphatidic acid recptor 1 (LPA1) is the most widely expressed.<ref name= "Mills"/> LPA,1 is coupled to a heterotrimeric G protein on the intracellular side of the cell membrane. The three G alpha proteins that LPA1 couples to are Gi, Gq, and G12/13.<ref name= "Moolenaar"> DOI: 10.1002/bies.20081 </ref> From these three G proteins many signal transduction pathways are activated. The downstream effects of Gi include cell proliferation, survival, and migration.<ref name= "Mills"/> Gi leads to cell proliferation by the activation of the RAS-mediated MAPK cascade. <ref name= "Mills"> DOI:10.1038/nrc1143 </ref> The alpha subunit Gq signals the inhibition of gap-junctional communication. The pathways activated by G12/13 include cell proliferation and morphology.<ref name= "Mills"/> 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.<ref name= "Chrencik"/>

LPA1 is part of the larger EDG (endothelial differentiation gene) family, which includes the sphingosine 1-phosphate receptors. Significantly more research has been done on S1P1 than other receptors in this family. S1P1 is coupled to the same heterotrimeric G protein that LPA1 is, and both receptors are involved in growth-related activity and cytoskeletal functions. <ref name= "Joetzl" > PMID:9837849 </ref>

== Clinical Relevance ==

=== Cancer ===
Many of the functions of LPA1, i.e. cell proliferation, survival, and morphology, are implicated in cancers. LPA acts as a tumor mitogen and an inducer of tumor-derived cytokine to support the metastasis (spreading) of breast and ovarian cancer to bones. Inhibition of LPA1 can significantly reduce this progression, and therefore may be a promising treatment for patients with bone metastasis. <ref name= "Boucharaba"> DOI: 10.1073/pnas.0600979103 </ref> LPA does not have an effect on primary tumor size. <ref name= "Jean > DOI: 10.1093/jnci/djs319 </ref>

===Pain===

When 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). The actiavtion of ROCK is a required step in the pathway in the stimulation of neurotic pain. When ROCK was inhibited it meant that the rest of the pathway would not work according to plan. 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.<ref name= "Inoue"> DOI:10.1038/nm1060 </ref>. Another use of LPA is it can help in stimulation of cell migration <ref name= "Moolenaar"/>.

=== Fibrosis ===
To gain a better understand the role the LPA plays in fibrosis, a study was done with mice who had contracted fibrosis <ref name= "Tager"> PMID:18066075 </ref>. Idiopathic pulmonary fibrosis (IPF) has high rates of mortality. Research has been done to study the pathway of the LPA-LPA1 in fibroblast migration ([https://en.wikipedia.org/wiki/Wound_healing Wound Healing]). In the injured lungs, the IPF, fibroblast can be activated. In the lungs genes related to cell migration can be unregulated. The fibroblast migration can be regulated by LPA. The bronchoalveolar lavage (BAL) in mice that had fibrosis was elevated. LPA1 plays an active role between lung injury and contracting pulmonary fibrosis. LPA has the ability to lead to a vascular leak after an initial injury which can lead to fibrosis. This study's findings shows that LPA1 is part of a link between lung injury and [http://www.nature.com/nm/journal/v14/n1/fig_tab/nm1685_F4.html pulmonary fibrosis] <ref name= "Tager"/>.

== Endocannabinoids ==

The endocannabinoid 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.<ref name= "Chrencik"/> Both the cannabinoid receptors and the LPA receptors have a preference for long unsaturated acyl chains.<ref name= "Chrencik"/> The polar amino acid <scene name='72/721545/210/1'>Trp210</scene> in the binding pocket is unique to the lysophospholipid and cannabinoid receptors.

[[Image:2-AG.png|220px|right|thumb|'''Figure 4:''' 2-arachidonylglycerol (2-AG)]]

A major cannabinoid signaling molecule, 2-arachidonyl glycerol (2-AG, Figure 4), can be phosphorylated into 2-arachidonyl phosphatidic acid (2-ALPA). 2-ALPA has a similar structure to LPA, and is able to bind in the LPA1 receptor binding pocket. 2-ALPA binding to LPA1 causes the same downstream signaling that the LPA molecule does, effectively connecting these two systems. Promiscuous ligand binding between these two pathways has potential functional and therapeutic implications.<ref name= "Chrencik"/>

== References ==
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{{Sandbox_Reserved_CH462_Central_Metabolism}}
==Human ''Lysophosphatodic Acid'' Receptor 1==

==Lysophosphatodic Acid==
[[Image:LPA.png|200px|left|thumb|'''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 <ref name="Moolenaar"> DOI: 10.1002/bies.20081 </ref>.

<scene name='72/721546/Lpa-helices/1'>Helices</scene>
==Structure==
<StructureSection load='4z34' size='340' side='right' caption='LPA' scene=''>
===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 <ref name= "Chrencik"> PMID: 26091040 </ref>.
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. [[Image:LPA1vs. SAP1.png|300px|left|thumb|'''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 <ref name= "Chrencik"/>.

== Function ==

== Relevance ==
</StructureSection>

==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 ,ref name= "Chrencik"/>. LPA receptors are commonly found in serum and saliva. <ref name= "Moolenaar"/>.
===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.<ref name= "Inoue"> DOI:10.1038/nm1060 </ref>. Another use of LPA is it can help in stimulation of cell migration <ref name= "Moolenaar" </ref>.

=== Fibrosis ===
To look at the effects of LPA on fibrosis, there was a study done with mice <ref> PMID:18066075 </ref>. It was seen that with targeted deletion of LPA receptors the mice would be cured from fibrosis. Mice who had fibrosis were given LPA1 regulated LPA-induced fibroblast. Over time the mice who had fibrosis began to have their lungs repaired. The amount of fluid in their lungs decreased.

== References ==
<references/>