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Lysophosphatidic Acid Receptor 3 (LPA3): Signaling and Phosphorylation Sites
K Helivier Solís1, M Teresa Romero-Ávila1, Ruth Rincón-Heredia2
1Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ap. Postal 70-600, Ciudad de México 04510, Mexico.
International Journal of Molecular Sciences
|June 27, 2024
Summary
Lysophosphatidic acid receptor 3 (LPA3) signaling involves calcium increases and ERK phosphorylation. LPA3 receptor regulation includes distinct internalization pathways and specific phosphorylation sites crucial for beta-arrestin binding.
Area of Science:
- Cellular signaling and receptor biology
- G protein-coupled receptor (GPCR) research
- Molecular pharmacology
Background:
- Lysophosphatidic acid (LPA) is a bioactive lipid mediator involved in various physiological processes.
- LPA receptors, particularly LPA3, play critical roles in cellular responses.
- Understanding LPA3 receptor signaling and regulation is essential for elucidating its physiological functions.
Purpose of the Study:
- To investigate the signaling pathways activated by LPA3 receptors in TREx HEK 293 cells.
- To characterize the regulation of LPA3 receptor activity, including internalization and phosphorylation.
- To identify specific phosphorylation sites on the LPA3 receptor and their potential role in β-arrestin association.
Main Methods:
- Expression of LPA3 receptors in TREx HEK 293 cells.
- Measurement of intracellular calcium mobilization and ERK phosphorylation.
- Assessment of receptor internalization using Pitstop 2 (clathrin heavy chain inhibitor).
- Analysis of β-arrestin association and receptor phosphorylation using mass spectrometry.
Main Results:
- LPA stimulation increased intracellular calcium and ERK phosphorylation via pertussis toxin-insensitive pathways.
- Phorbol myristate acetate, but not LPA, desensitized LPA3-mediated calcium signaling and induced receptor internalization.
- LPA triggered rapid β-arrestin-LPA3 receptor association and specific phosphorylation at intracellular loop 3 and carboxyl terminus sites.
- Identified phosphorylation sites (S221, T224, S225, S229, S321, S325, S331, T333, S335, Y337, S343) are located within predicted β-arrestin binding domains.
Conclusions:
- LPA3 receptor signaling is mediated by pertussis toxin-insensitive G proteins.
- Distinct mechanisms regulate LPA3 receptor internalization, influenced by agonists and clathrin-mediated pathways.
- Specific phosphorylation of LPA3 receptor sites is critical for β-arrestin recruitment, providing insights into receptor regulation.
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