Lysophospholipid (LPA) receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Abstract

Lysophosphatidic acid (LPA) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid Receptors [50, 18]) are activated by the endogenous phospholipid LPA. The first receptor, LPA1, was identified as ventricular zone gene-1 (vzg-1) [38], leading to deorphanisation of members of the endothelial differentiation gene (edg) family as other LPA receptors along with sphingosine 1-phosphate (S1P) receptors. Additional LPA receptor GPCRs were later identified. Gene names have been codified as LPAR1, etc. to reflect the receptor function of proteins. The crystal structure of LPA1 was solved and demonstrates extracellular LPA access to the binding pocket, consistent with proposed delivery via autotaxin [12]. These studies have also implicated cross-talk with endocannabinoids via phosphorylated intermediates that can also activate these receptors. The identified receptors can account for most, although not all, LPA-induced phenomena in the literature, indicating that a majority of LPA-dependent phenomena are receptor-mediated. Binding affinities of unlabeled, natural LPA and AEAp to LPA1 were measured using backscattering interferometry (pKd = 9) [73]. Binding affinities were 77-fold lower than than values obtained using radioactivity [111]. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. Independent validation by multiple groups has been reported in the peer-reviewed literature for all six LPA receptors described in the tables, including further validation using a distinct read-out via a novel TGFα "shedding" assay [45]. LPA has also been described as an agonist for the transient receptor potential (Trp) ion channel TRPV1 [76] and TRPA1 [53]. LPA was originally proposed to be a ligand for GPCR35, but data show that in fact it is a receptor for CXCL17 [68]. All of these proposed non-GPCR receptor identities require confirmation and are not currently recognized as bona fide LPA receptors.