LPA<sub>3</sub>: Pharmacodynamic Differences Between Lysophosphatidic Acid and Oleoyl-Methoxy Glycerophosphothionate: Biased Agonism, Two Sites
<b>Background:</b> Lysophosphatidic acid (LPA) receptor 3 (LPA<sub>3</sub>) is involved in many physiological and pathophysiological actions of this bioactive lipid, particularly in cancer. The actions of LPA and oleoyl-methoxy glycerophosphothionate (OMPT) were compared in L...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-12-01
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| Series: | Receptors |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2813-2564/3/4/29 |
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| Summary: | <b>Background:</b> Lysophosphatidic acid (LPA) receptor 3 (LPA<sub>3</sub>) is involved in many physiological and pathophysiological actions of this bioactive lipid, particularly in cancer. The actions of LPA and oleoyl-methoxy glycerophosphothionate (OMPT) were compared in LPA<sub>3</sub>-transfected HEK 293 cells. <b>Methods</b>: Receptor phosphorylation, ERK 1/2 activation, LPA<sub>3</sub>-β-arrestin 2 interaction, and changes in intracellular calcium were analyzed. <b>Results</b>: Our data indicate that LPA and OMPT increased LPA<sub>3</sub> phosphorylation, OMPT being considerably more potent than LPA. OMPT was also more potent than LPA to activate ERK 1/2. In contrast, OMPT was less effective in increasing intracellular calcium than LPA. The LPA-induced LPA<sub>3</sub>-β-arrestin 2 interaction was fast and robust, whereas that induced by OMPT was only detected at 60 min of incubation. LPA- and OMPT-induced receptor internalization was fast, but that induced by OMPT was more marked. LPA-induced internalization was blocked by Pitstop 2, whereas OMPT-induced receptor internalization was partially inhibited by Pitstop 2 and Filipin and entirely by the combination of both. When LPA-stimulated cells were rechallenged with 1 µM LPA, hardly any response was detected, i.e., a “refractory” state was induced. However, a conspicuous and robust response was observed if OMPT was used as the second stimulus. <b>Conclusions:</b> The differences in these agents’ actions suggest that OMPT is a biased agonist. These findings suggest that two binding sites for these agonists might exist in the LPA<sub>3</sub> receptor, one showing a very high affinity for OMPT and another likely shared by LPA and OMPT (structural analogs) with lower affinity. |
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| ISSN: | 2813-2564 |