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Lysophospholipid (LPA) receptors C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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Lysophosphatidic acid (LPA) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid Receptors [5,19,29,45]) are activated by the endogenous phospholipid LPA. The first receptor, LPA1, was identified as ventricular zone gene-1 (vzg-1) [13], This discovery represented the beginning of the de-orphanisation of members of the endothelial differentiation gene (edg) family, as other LPA and sphingosine 1-phosphate (S1P) receptors were found. Five additional LPA receptors (LPA2,3,4,5,6) have since been identified [29] and their gene nomenclature codified for human LPAR1, LPAR2, etc. (HUGO Gene Nomenclature Committee, HGNC) and Lpar1, Lpar2, etc. for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function of their corresponding proteins. The high-resolution structures of LPA1 [1-3,28] and LPA6 [6,41] determined by both X-ray crystallography and cryo-electron microscopy, are solved and indicate that LPA accesses the extracellular binding pocket, consistent with its proposed delivery via autotaxin [3]. These studies have also implicated crosstalk with endocannabinoids via phosphorylated intermediates that can also activate these receptors. The binding affinities to LPA1 of unlabeled, natural LPA and anandamide phosphate (AEAp) were measured using backscattering interferometry (pKd = 9) [30,38]. Utilization of this method indicated affinities that were 77-fold lower than when measured using radioactivity-based protocols [44]. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. admilparant (BMS-986278) [4], a selective LPA1 receptor antagonist, is currently in Phase III trials for pulmonary fibrosis. Other LPA1-targeting drugs such as BMS-986020 were discontinued due to hepatotoxicity [36], while preclinical candidates like PIPE 791 [37] are being explored for neurological and fibrotic diseases. Multiple groups have independently published validation of all six LPA receptors described in these tables, and further validation was achieved using a distinct read-out via a novel TGFα "shedding" assay [16]. Moreover, LPA has also been described as an agonist for the transient receptor potential (Trp) ion channels TRPV1 [32] and TRPA1 [21]. All of these proposed non-GPCR receptor identities require confirmation and are not currently recognized as bona fide LPA receptors.
Receptors
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LPA1 receptor
C
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LPA2 receptor
C
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LPA3 receptor
C
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LPA4 receptor
C
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LPA5 receptor
C
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LPA6 receptor
C
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Further reading
Citation information
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.
Ki16425 [34], VPC12249 [14] and VPC32179 [12] have dual antagonist activity at LPA1 and LPA3 receptors. There is growing evidence for in vivo efficacy of these chemical antagonists in several disorders, including fetal hydrocephalus [46], fetal hypoxia [15], lung fibrosis [33], systemic sclerosis [33] and atherosclerosis progression [24]. LPA2 selective antagonist SAR100842 [25], and LPA1 selective agonist UCM-05194 [10], are proposed for therapy of systemic sclerosis and neuropathic pain, respectively. The LPA2 selective agonist, GRI977143, shows efficacy in an animal model of multiple sclerosis [39]. The LPA5 selective antagonist, AS2717638, is effective in pain models [17]. Antidepressants, amitriptyline, clomipramine, and mianserin, are reported to show profibrotic responses via LPA1 [35].