Sandbox Reserved 1174: Difference between revisions

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== Function ==

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 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 ~~(Figure 2)~~. The downstream effects of Gi are cell proliferation, cell survival, cell migration, and morphological changes. Gq signals the inhibition of gap-junctional communication. Those of G12/13 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.<ref name= "Chrencik"> DOI: 10.1016/j.cell.2015.06.002 </ref>

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 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 are cell proliferation, cell survival, cell migration, and morphological changes. Gq signals the inhibition of gap-junctional communication. Those of G12/13 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.<ref name= "Chrencik"> DOI: 10.1016/j.cell.2015.06.002 </ref>

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

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== Structure of LPA1==

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/1'>fatty acid</scene> bound to it in orange. There are more <scene name='72/721545/Polarity/1'>polar</scene> (red) resides on the intercellular and extracellular areas of the receptor, while most residues positioned inside the membrane are hydrophobic (blue).

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/1'>fatty acid</scene> bound to it in orange. There are more <scene name='72/721545/Polarity/1'>polar</scene> (red) resides on the intercellular and extracellular areas of the receptor, while most residues positioned inside the membrane are hydrophobic (blue).

[[Image:LPA_in_membrane.fw.png|200px|center|thumb|'''Figure 2:''' LPA in the Phospholipid Bilayer]]

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=== Structural Stabilization ===

There are many different stabilizing factors in the structure of this receptor. There are three native <scene name='72/721545/Disulfides/1'>disulfide bonds</scene> in the extracellular region. One of these bonds constrains the N terminal helix to extracellular loop 2. The <scene name='72/721545/N-terminus/1'>N-terminus</scene> functions like a cap on the extracellular side of the protein, packing tightly against ECL1 and ECL2. It also provides <scene name='72/721545/34_39_40/2'>polar amino acids</scene> that interact with the ligand when bound.

There are many different stabilizing factors in the structure of this receptor. There are three native <scene name='72/721545/Disulfides/1'>disulfide bonds</scene> in the extracellular region.<ref name= "Chrencik"/> One of these bonds constrains the N terminal helix to extracellular loop 2. The <scene name='72/721545/N-terminus/1'>N-terminus</scene> functions like a cap on the extracellular side of the protein, packing tightly against ECL1 and ECL2. It also provides <scene name='72/721545/34_39_40/2'>polar amino acids</scene> that interact with the ligand when bound.

=== Binding Pocket ===

The <scene name='72/721545/Ligand/1'>binding pocket</scene> for LPA inside the receptor consists of both polar and nonpolar residues. There are <scene name='72/721545/All_polar_interactions/4'>polar</scene> residues on the N terminus and along one side of the binding pocket (<scene name='72/721545/All_polar_interactions/3'>polar residues</scene>). There is also a <scene name='72/721545/Hydrophobic_pocket/2'>hydrophobic pocket</scene> that interacts with the long acyl chain of LPA.

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

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== 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.<ref name= "Chrencik"/>

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.<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. <ref name= "Chrencik"/>

Promiscuous ligand binding between these two pathways has potential functional and therapeutic implications. Certain endocannabinoids are able to the LPA1 receptor and cause the same downstream signalling that the LPA signalling molecule does.

Sandbox Reserved 1174: Difference between revisions

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@@ Line 15: / Line 15: @@
 == Function ==
-Of the six LPA G-protein coupled receptors, LPA<sub>1</sub> is the most widely expressed. Lysophosphatidic acid receptor 1 is coupled to a heterotrimeric G protein. The three G alpha proteins that LPA<sub>1</sub> couples to are G<sub>i</sub>, G<sub>q</sub>, and G<sub>12/13</sub>.<ref name= "Moolenaar"> DOI: 10.1002/bies.20081 </ref> From these three G proteins many signal transduction pathways are activated (Figure 2). The downstream effects of G<sub>i</sub> are cell proliferation, cell survival, cell migration, and morphological changes. G<sub>q</sub> signals the inhibition of gap-junctional communication. Those of G<sub>12/13</sub> 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.<ref name= "Chrencik"> DOI: 10.1016/j.cell.2015.06.002 </ref>
+Of the six LPA G-protein coupled receptors, LPA<sub>1</sub> is the most widely expressed. Lysophosphatidic acid receptor 1 is coupled to a heterotrimeric G protein. The three G alpha proteins that LPA<sub>1</sub> couples to are G<sub>i</sub>, G<sub>q</sub>, and G<sub>12/13</sub>.<ref name= "Moolenaar"> DOI: 10.1002/bies.20081 </ref> From these three G proteins many signal transduction pathways are activated. The downstream effects of G<sub>i</sub> are cell proliferation, cell survival, cell migration, and morphological changes. G<sub>q</sub> signals the inhibition of gap-junctional communication. Those of G<sub>12/13</sub> 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.<ref name= "Chrencik"> DOI: 10.1016/j.cell.2015.06.002 </ref>
 LPA<sub>1</sub> is part of the larger EDG (endothelial differentiation gene) family which includes the sphingosine 1-phosphate receptors. Compare to S1P…
@@ Line 25: / Line 25: @@
 == Structure of LPA<sub>1</sub>==
-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/1'>fatty acid</scene> bound to it in orange. There are more <scene name='72/721545/Polarity/1'>polar</scene> (red) resides on the intercellular and extracellular areas of the receptor, while most residues positioned inside the membrane are hydrophobic (blue).
+The LPA<sub>1</sub> 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/1'>fatty acid</scene> bound to it in orange. There are more <scene name='72/721545/Polarity/1'>polar</scene> (red) resides on the intercellular and extracellular areas of the receptor, while most residues positioned inside the membrane are hydrophobic (blue).
 [[Image:LPA_in_membrane.fw.png|200px|center|thumb|'''Figure 2:''' LPA in the Phospholipid Bilayer]]
@@ Line 31: / Line 31: @@
 === Structural Stabilization ===
-There are many different stabilizing factors in the structure of this receptor. There are three native <scene name='72/721545/Disulfides/1'>disulfide bonds</scene> in the extracellular region. One of these bonds constrains the N terminal helix to extracellular loop 2. The <scene name='72/721545/N-terminus/1'>N-terminus</scene> functions like a cap on the extracellular side of the protein, packing tightly against ECL1 and ECL2. It also provides <scene name='72/721545/34_39_40/2'>polar amino acids</scene> that interact with the ligand when bound.
+There are many different stabilizing factors in the structure of this receptor. There are three native <scene name='72/721545/Disulfides/1'>disulfide bonds</scene> in the extracellular region.<ref name= "Chrencik"/> One of these bonds constrains the N terminal helix to extracellular loop 2. The <scene name='72/721545/N-terminus/1'>N-terminus</scene> functions like a cap on the extracellular side of the protein, packing tightly against ECL1 and ECL2. It also provides <scene name='72/721545/34_39_40/2'>polar amino acids</scene> that interact with the ligand when bound.
 === Binding Pocket ===
 The <scene name='72/721545/Ligand/1'>binding pocket</scene> for LPA inside the receptor consists of both polar and nonpolar residues. There are <scene name='72/721545/All_polar_interactions/4'>polar</scene> residues on the N terminus and along one side of the binding pocket (<scene name='72/721545/All_polar_interactions/3'>polar residues</scene>). There is also a <scene name='72/721545/Hydrophobic_pocket/2'>hydrophobic pocket</scene>  that interacts with the long acyl chain of LPA.
 === Sphingosine-1-Phosphate Receptor ===
@@ Line 62: / Line 59: @@
 == 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.<ref name= "Chrencik"/>
+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.<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. <ref name= "Chrencik"/>
 Promiscuous ligand binding between these two pathways has potential functional and therapeutic implications. Certain endocannabinoids are able to the LPA<sub>1</sub> receptor and cause the same downstream signalling that the LPA signalling molecule does.