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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 bind 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(link) which includes the more widely known sphingosine 1-phopshate receptors.

Structure

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. Within these helices is an amphiphilic binding pocket enabling the LPA molecule to bind.

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. 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. 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.

Function

The LPA₁ receptor has been found to initiate downstream signaling cascades with three G proteins that signal for cell proliferation, survival, and migration. 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. Despite this receptor being expressed throughout the body, LPA₁ has been found to be expressed highly in neural tissue, aiding in Schwann cell migration and myelination, formation of synapses, and glial cell growth. Recent studies have also found that the LPA₁ receptor is important in pain signal initiation via a ROCK pathway.

Disease Relevance

The LPA₁ receptor, depending on its level of expression, has been linked to both protective functions in the presence of a disease as well as causing a particular illness. For example, in patients with heart diseases, LPA₁ has been found to communicate with PI3K, PKB, and ERK to induce a hypertrophic response in the heart in order to offset reduced heart contractions. In addition, due to LPA₁'s function of pain signaling, overexertion of this protein can cause both allodynia or hyperalgesia, common symptoms of multiple sclerosis or a stroke. 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. Lastly, due to the function of LPA₁ in myelinating Schwann cells, mutation of the receptor can also lead to a decrease in prepulse inhibition, a general sign of schizophrenia.

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%. 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. 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. 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. 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.

Endocannabinoid Receptor 1

LPA₁ also is closely related to the cannabinoid receptor CB1. This close relation gives CB1 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. Specifically, complementary access to the LPA₁ binding pocket can be achieved by phosphorylated CB1 ligand analogs, while complementary access to the CB1 binding site required 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.