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Introduction

Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA₁) is a G protein-coupled receptor and one of 6 different LPA receptors (LPA₁-LPA₆) that binds the phospholipid derivative lysophosphatidic acid (LPA), a signaling molecule that acts as a potent mitogen upon binding to one of its six receptors.^[1] LPA₁ is part of the larger EDG receptor family which includes the more widely known sphingosine 1-phopshate receptors.

Structure

Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA₁ receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.

The LPA₁ receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA₁ contains seven alpha helices which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. The amino terminus of this protein is located on the extracellular side of the membrane, while the carboxyl terminus is located on the intracellular side of the membrane.^[2]. Within these helices is an amphipathic binding pocket which stabilizes the binding of its ligand, LPA.

Key Ligand Interactions

Three separate interactions with an antagonist of LPA₁, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.^[1] In addition, interplay between causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.^[1] While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA₁ receptor. forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.^[1]

Function

The LPA₁ receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA₁ receptor has been found to have physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor has been found to initiate downstream signaling cascades with three G_α proteins: G_i/o, G_q/11, and G_12/13. These G_α proteins begin signaling cascades with molecules such as phospholipase C and MAPK that signal for cell proliferation, survival, and migration. ^[3].Despite this receptor being expressed throughout the body, LPA₁ has been found to be expressed highly in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the cerebral cortex and the growth, survival, and migration of neural progenitor cells through its different G-protein regulated pathways.^[4]. Finally, LPA1 receptors expressed in neural tissue aid in Schwann cell migration and myelination through a signaling pathway with the Rac1 G-protein.^[5].

Disease Relevance

Because LPA₁ is expressed in so many tissues throughout the body, it has been linked to the symptoms and progression of several different diseases and disorders. For example, due to LPA₁'s role in pain signaling, overexpression of this protein can cause both allodynia or hyperalgesia, common symptoms of multiple sclerosis or strokes. In addition, since LPA₁ helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in prepulse inhibition, a general sign of schizophrenia.^[6].Lastly, because of the mitogen signaling activity of LPA₁, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA₁, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by hypoxic tumors creating lactic acid, LPA₁ activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.^[7]. In contrast, the LPA₁ receptor has also been found to induce protective functions in the presence of a particular illness. For example, in patients with heart disease, LPA₁ has been found to communicate with PI3K, PKB, and ERK to create a hypertrophic response in the heart in order to offset reduced heart contractions.

Receptor Comparison

Sphingosine 1-Phosphate Receptor

LPA₁ belongs to the EDG (endothelial differentiation gene) family of lysophospholipid receptors. This family also includes the sphingosine 1-phosphate receptor 1 (S1P₁), which has many structural similarities to LPA₁. In fact, the transmembrane regions share a sequence identity of 41%. ^[8] A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic S1P ligand enters S1P₁ via the membrane, LPA₁ has an extracellular opening that allows LPA access from the extracellular space ^[1]. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of , which is positioned 3 angstroms closer to TMVII compared to S1P₁, and a repositioning of , resulting in a divergence of 8 angstroms from S1P₁ ^[1]. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access for LPA₁. Additionally, ECL0 is helical in S1P₁, but lacks secondary structure in LPA₁. This increased flexibility that results further promotes favorable access from the extracellular space ^[1].

Endocannabinoid Receptor 1

LPA₁ also is closely related to the first of the cannabinoid receptors. This close relation gives CB₁ (Cannabinoid Receptor 1) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation ^[1]. Specifically, complementary access to the LPA₁ binding pocket can be achieved by phosphorylated CB₁ ligand analogs, while complementary access to the CB₁ binding site requires dephosphorylation of LPA₁ ligand analogs. In both cases, a ligand could serve as a primary receptor modulator and a simultaneous prodrug for a different receptor ^[1].

located within the hydrophobic binding pocket of LPA₁ may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution. ^[1] Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. ^[9]

A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB₁'s most abundant endogenous ligands into the LPA₁ binding pocket. ^[1] Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA₁ and CB₁ are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups. ^[1]