LPA receptor signaling: pharmacology, physiology, and pathophysiology

Abstract

Lysophosphatidic acid (LPA) is a small ubiquitous lipid found in vertebrate and nonvertebrate organisms that mediates diverse biological actions and demonstrates medicinal relevance. LPA's functional roles are driven by extracellular signaling through at least six 7-transmembrane G protein-coupled receptors. These receptors are named LPA1-6 and signal through numerous effector pathways activated by heterotrimeric G proteins, including Gi/o, G12/13, Gq, and Gs LPA receptor-mediated effects have been described in numerous cell types and model systems, both in vitro and in vivo, through gain- and loss-of-function studies. These studies have revealed physiological and pathophysiological influences on virtually every organ system and developmental stage of an organism. These include the nervous, cardiovascular, reproductive, and pulmonary systems. Disturbances in normal LPA signaling may contribute to a range of diseases, including neurodevelopmental and neuropsychiatric disorders, pain, cardiovascular disease, bone disorders, fibrosis, cancer, infertility, and obesity. These studies underscore the potential of LPA receptor subtypes and related signaling mechanisms to provide novel therapeutic targets.

Keywords: atherosclerosis; autotaxin; brain lipids; cancer; fibrosis; lysophosphatidic acid; lysophospholipid; obesity; pain; reproduction.

Fig. 1.

Summary of the major routes of LPA synthesis and the activated signaling pathways via the six cognate LPA receptors. Enzymes are indicated in red. PC, phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine; PLD, phospholipase D.

Fig. 2.

Effects of LPA receptor agonists and antagonists. LPA receptor modulating compounds are classified according to their potency against each receptor, LPA₁–LPA₆. Ranges of compound EC₅₀, IC₅₀, or K_i values are given on the x axis, progressing from strong antagonism on the left to strong agonism on the right. A subset of these compounds is shown in more detail in Table 2. This graph was prepared using GraphPad Prism software. Cmpd, compound; NPSPA, N-palmitoyl serine phosphoric acid; NPTyrPA, N-palmitoyl tyrosine phosphoric acid; NAEPA, N-acyl ethanolamide phosphate; AO-LPA 12b, sn-2-aminooxy analog 12b; a-FMP, α-fluoromethylene phosphonate; a-HMP, α-hydroxymethylene phosphonate; TPA, thiophosphatidic acid; DDP, dodecyl phosphate; a-MP, α-methylene phosphonate; ODP, octadecenyl phosphate; TP 18:1, oleoyl-thiophosphate; BrP-LPA 19b, α-bromomethylene phosphonate analog 19b; TDP, tetradecyl phosphonate; FDP, farnesyl diphosphate.