Lysophosphatidylserine analogues differentially activate three LysoPS receptors

Abstract

Lysophosphatidylserine (1-oleoyl-2 R-lysophosphatidylserine, LysoPS) has been shown to have lipid mediator-like actions such as stimulation of mast cell degranulation and suppression of T lymphocyte proliferation, although the mechanisms of LysoPS actions have been elusive. Recently, three G protein-coupled receptors (LPS1/GPR34, LPS2/P2Y10 and LPS3/GPR174) were found to react specifically with LysoPS, raising the possibility that LysoPS serves as a lipid mediator that exerts its role through these receptors. Previously, we chemically synthesized a number of LysoPS analogues and evaluated them as agonists for mast-cell degranulation. Here, we used a transforming growth factor-α (TGFα) shedding assay to see if these LysoPS analogues activated the three LysoPS receptors. Modification of the serine moiety significantly reduced the ability of the analogues to activate the three LysoPS receptors, whereas modification of other parts resulted in loss of activity in receptor-specific manner. We found that introduction of methyl group to serine moiety (1-oleoyl-lysophosphatidylallothreonine) and removal of sn-2 hydroxyl group (1-oleoyl-2-deoxy-LysoPS) resulted in reduction of reactivity with LPS1 and LPS3, respectively. Accordingly, we synthesized a LysoPS analogue with the two modifications (1-oleoyl-2-deoxy-lysophosphatidylallothreonine) and found it to be an LPS2-selective agonist. These pharmacological tools will definitely help to identify the biological roles of these LysoPS receptors.

Lysophosphatidylserine receptor P2Y10: A G protein‐coupled receptor that mediates eosinophil degranulation

“…LysoPS is a member of a family of endogenous lipid mediators that binds to and activates P2Y10, GPR34, and GPR174. All three of these GPCRs have recently been deorphanized to be activated by LysoPS on the basis of TGF‐α shedding capability . However, the role of this bioactive mediator in both physiological and pathological conditions has remained largely unanswered.…”

Phospholipid localization implies microglial morphology and function via Cdc42 in vitro

“…18:1‐sphingosine‐1‐phosphate (S1P) was from Cayman Chemical (Ann Arbor, MI, USA). LysoPS with various fatty acids [capric (10:0), lauric (12:0), myristic (14:0), palmitic (16:0) and palmitoleic (16:1)] and LysoPS analogs with oleic acid (18:1) including deoxy‐LysoPS were synthesized as previously described (Iwashita et al, ; Uwamizu et al, ). Eicosatetraenoic (20:4) and docosahexaenoic (22:6) were provided by Ono Pharmaceutical Co. (Osaka, Japan).…”

Structure–Activity Relationships of Lysophosphatidylserine Analogs as Agonists of G-Protein-Coupled Receptors GPR34, P2Y10, and GPR174

“…22 This idea seemed reasonable because several LysoPS analogues containing simple modifications in individual modules activated the three LysoPS receptor subtypes differently. 21 Therefore, starting from the endogenous ligand (1, 1-oleoyl-LysoPS), we optimized the structures of the individual modules, as well as their linkages. We focused on unsaturated fatty acid derivatives because, like other lysophospholipid receptors for lysophosphatidic acid (LPA) and lysophosphatidylinositol (LPI), 23 LysoPS receptors favor LysoPS with an unsaturated fatty acid component rather than a saturated fatty acid moiety.…”

“…Analogues modified at the serine moiety, such as commercially available and endogenous 1-oleoyl-lysophosphatidylethanolamine (LysoPE), and chemically synthesized derivatives, including LysoPS Me ester (7a), LysoPS CH 2 OH (7b), and lysoPDS (D-serine) (7c) ( Figure 6 and Table 1), showed little activity toward the three receptors (except 7a toward P2Y10), suggesting that the amino acid functionality is critical for activation of LysoPS receptors. 21 Next, we synthesized LysoPS analogues with a methyl group at the β-position of serine, corresponding to modification of Lserine to threonine or allothreonine ( Figure 6). 22 As already reported, 21 when the stereochemistry of the methyl group was R (L-threonine), LysoPT (7d) showed no activation potency toward the three LysoPS receptors, though 7d was reported to be a strong inducer of mast cell degranulation.…”

“…21 Next, we synthesized LysoPS analogues with a methyl group at the β-position of serine, corresponding to modification of Lserine to threonine or allothreonine ( Figure 6). 22 As already reported, 21 when the stereochemistry of the methyl group was R (L-threonine), LysoPT (7d) showed no activation potency toward the three LysoPS receptors, though 7d was reported to be a strong inducer of mast cell degranulation. 22 The (S)-methyl analogue (i.e., allo-threonine), LysoPalloT (7e), showed reduced P2Y10 activation activity and apparent GPR174 activation activity, though interestingly, it showed no mast cell degranulation activity.…”