The status of the lysophosphatidic acid receptor type 1 (LPA₁R)

Abstract

Lysophospholipids are lipid molecules that are receiving growing attention because, in addition to their structural function in the cell membrane, they are now regarded as important regulators for diverse biological functions through activation of specific receptors. These receptors have been characterized during the last two decades as G protein-coupled receptors (GPCRs) and, among them, two families stand out: lysophosphatidic acid (LPA 1-6 ) and sphingosine 1-phoshate (S1P 1-5 ) receptors. Despite their interest, the high structural similarity between them has restrained the development of selective and high affinity ligands and therefore the elucidation of the role of these receptors in the central nervous system (CNS). This review provides an overview about the different LPA receptors with a special focus on the LPA 1 subtype from a medicinal chemistry perspective. It summarizes the most recent developments in the search for selective and specific agonists and antagonists of the LPA 1 receptor and highlights their current status in the drug development pipeline.

Mechanisms of lysophosphatidylcholine‐induced demyelination: A primary lipid disrupting myelinopathy

“…We found that neither autotaxin nor LPAR antagonists attenuated LPC‐induced toxicity. In addition, most of the LPAR1–6 signaling is sensitive to either pertussis toxin or Rho signaling mechanisms (Gonzalez‐Gil et al, ; Lee, Rivera, Gardell, Dubin, & Chun, ), which also did not attenuate LPC‐induced injury (Figure ).…”

Autotaxin-Lysophosphatidic Acid: From Inflammation to Cancer Development

“…Cancer cells have a higher LPA receptor content on their cell surface compared to normal and benign cells and a downregulated expression of LPPs [ 128 ]. Therefore, targeting LPA signaling through these components is currently under study and constantly reviewed [ 4 , 127 , 129 – 132 ]. In this section, we summarize some of the drugs studied regarding ATX inhibition and LPA receptor antagonism ( Table 1 ).…”

“…LPA activates at least six G-coupled protein receptors (LPA 1–6 ) stimulating different signaling pathways through heterotrimeric G proteins such as G i/0 , G 12/13 , G q/11 , and G s . The outcome of LPA signaling is dependent on cellular context and impacts on biological processes such as wound healing, differentiation, neurogenesis, and survival, to name a few [ 4 ]. Due to its small structure, LPA is water soluble and concentrations > 5 μ M have been reported in serum; concentrations < 1 μ M have been found in other biofluids such as plasma, saliva, follicular fluid, cerebrospinal fluid, and malignant effusions [ 5 – 7 ].…”

LPA signaling is regulated through the primary cilium: a novel target in glioblastoma

“…To test this hypothesis, immunoprecipitation analysis was performed in shCon, shIFT88, and shKIF3B astrocytes transiently overexpressing 3xFLAG-LPAR1. Based on sequence similarity, LPAR1 is predicted to interact with Gαi, Gαq, and Gα12 ( 19 ). No interaction was detected between LPAR1 and Gαs.…”

“…LPA acts through binding of heterotrimeric G-protein coupled receptors (LPAR1-6). It was previously reported that LPAR1 can signal through Gαi, Gα12, and Gαq family members ( 18 , 19 ). LPA stimulates cell proliferation in astrocytes ( 20 ) and cancer cells ( 21 ).…”