Lysophosphatidic acid (LPA) receptors: signaling properties and disease relevance

Abstract

Lysophosphatidic acid (LPA), a water-soluble phospholipid, has gained significant attention in recent years since the discovery that it acts as a potent signaling molecule with wide-ranging effects on many different target tissues. There are currently five identified G protein-coupled receptors for LPA and more are undergoing validation. The complexity of the expression pattern and signaling properties of LPA receptors results in multiple influences on developmental, physiological, and pathological processes. This review provides a summary of LPA receptor signaling and current views on the potential involvement of this pathway in human diseases that include cardiovascular, cancer, neuropathic pain, neuropsychiatric disorders, reproductive disorders, and fibrosis. The involvement of LPA signaling in these processes implicates multiple, potential drug targets including LPA receptor subtypes and LPA metabolizing enzymes. Modulation of LPA signaling may thus provide therapeutic inroads for the treatment of human disease.

Figure 1

Summary of the downstream signaling pathways activated by known lysophosphatidic acid (LPA) receptors.

Figure 2

Protein sequence alignment and phylogenic tree of human lysophosphatidic acid receptors. (A) Multiple alignment of LPA₁ to LPA₅. The seven transmembrane domains of LPA₁ are shaded red, purple, blue, green, yellow, orange, and grey respectively. Critical residues for ligand interactions identified by mutagenesis studies are indicated with black arrows. (B) Phylogenic tree of the five known LPA receptors (LPA_1–5), two possible LPA receptors (P2Y5 and GPR87), an S1P receptor (S1P₁), and Rhodopsin.

Figure 3

Schematic summary of human diseases that are known or suspected to involve dysregulation of LPA signaling.