The LPA3 Receptor: Regulation and Activation of Signaling Pathways

Abstract

The lysophosphatidic acid 3 receptor (LPA₃) participates in different physiological actions and in the pathogenesis of many diseases through the activation of different signal pathways. Knowledge of the regulation of the function of the LPA₃ receptor is a crucial element for defining its roles in health and disease. This review describes what is known about the signaling pathways activated in terms of its various actions. Next, we review knowledge on the structure of the LPA₃ receptor, the domains found, and the roles that the latter might play in ligand recognition, signaling, and cellular localization. Currently, there is some information on the action of LPA₃ in different cells and whole organisms, but very little is known about the regulation of its function. Areas in which there is a gap in our knowledge are indicated in order to further stimulate experimental work on this receptor and on other members of the LPA receptor family. We are convinced that knowledge on how this receptor is activated, the signaling pathways employed and how the receptor internalization and desensitization are controlled will help design new therapeutic interventions for treating diseases in which the LPA₃ receptor is implicated.

Keywords: GRK; LPA3; PKC; lysophosphatidic acid; lysophosphatidic acid 3 receptor; receptor phosphorylation.

Figure 1

LPA structure. Chemical structure of 1-oleoyl-2-hydroxy-sn-glycerol-3-phosphate (LPA 18:1). Atoms in the chemical structure: Carbon (grey), Hydrogen (white), Oxygen (red), and Phosphorus (orange) (https://pubchem.ncbi.nlm.nih.gov/compound/Lysophosphatidic-acid) (https://molview.org). Accessed on 4 June 2021.

Figure 2

LPA receptors and G proteins. LPA receptors couple with different G proteins that activate distinct signaling pathways. PLC, phospholipase C; PI3K. phosphoinositide 3-kinase; AC, adenylyl cyclase. Created with BioRender.com.

Figure 3

Internalization of agonist-activated LPA₃ receptors. (1) Activation of LPA₃ with LPA and recruitment of a G protein. (2) Exposure of GPCR phosphorylation sites. (3) Recruitment of β-arrestin through interaction with phosphorylated sites. (4) Recruitment of the endocytic machinery that initiates receptor endocytosis. (5) Endocytosis of LPA₃ via endosomes. (6) Receptor-endosomal traffic to (7) lysosomal receptor degradation or (8) receptor recycling to the plasma membrane. Question marks indicate that there is little information on these processes, which are postulated in similarity to what has been defined for other receptors. Created with BioRender.

Figure 4

Signaling pathway of LPA₃ receptors. Activation of this receptor subtype with LPA promotes conformational changes favoring intense interaction with G_αq/11 and G_αi/o, which lead to activation of downstream signaling molecular entities. Abbreviations as in Figure 2. Created with BioRender.

Figure 5

LPA₃ receptor structure, domains and sites that regulate this receptor. Image shows the amino acid sequence and the organization of the LPA₃ receptor with three extracellular loops, three intracellular loops, the seven transmembrane domains, the extracellular amino terminus (-NH₂), and the intracellular carboxyl terminus (-COOH). Colored boxes indicate conserved motifs putatively relevant for activation and regulation of the LPA₃ receptor. Putative sites where LPA interacts with LPA₃ are shown in green, while proposed places where GPCRs could be recruiting G proteins are marked in blue and purple (R, arginine that is also part of the ERH motif). “Y” indicates a potential glycosylation site, and the line joining one of the cysteines to the membrane is a putative palmitoylation site.

Figure 6

In silico prediction of serine and threonine sites phosphorylated by GRK, PKA and PKC. LPA₃ structure is represented, showing (in red) the putative sites targeted by GRK and (in cerulean) putative sites phosphorylated by PKA or PKC.