Lysophosphatidic Acid Receptors (LPARs) Regulate Ocular Surface Ion Transport

Abstract

Purpose : The ocular surface epithelium contains ion transporters such as epithelial Na⁺ channel (ENaC), cystic fibrosis transmembrane conductance regulator (CFTR) Cl^- channel, and Ca²⁺-activated Cl^- channels (CaCCs) that regulate fluid transport. Lysophosphatidic acid receptors (LPARs) are a family of G-protein coupled receptors expressed widely across the body that play a major role in Ca²⁺ mobilization and cellular proliferation. Here we investigate the role of LPARs in ocular surface ion transport.

Methods : We tested the effects of selective LPARs modulators on mouse ocular surface ion transport using in vivo ocular surface potential difference (OSPD) measurements. Next, we studied LPAR₃ expression using immunostaining in both mouse and human cornea and conjunctiva.

Results : Linoleoyl lysophosphatidic acid 18:2 (LPA), a general LPARs agonist, induced a voltage change mimicking the Ca²⁺ agonist ATP-induced CaCCs activation. The LPA-induced CaCCs activation was blocked by Ki 16425, an LPAR_1-3 antagonist (Figure 1A). We determined this CaCCs activation was mediated by LPAR₃ specifically (Figure 1B). No compound influenced baseline OSPD or Na⁺ absorption mediated by ENaC. LPAR₃ is expressed in the mouse and human corneal and conjunctival epithelia (Figure 2).

Conclusions : Our results suggest that LPAR₃ stimulates Cl^- secretion via CaCCs activation and may play a role in the regulation of ocular surface hydration, therefore representing a novel potential therapeutic target for ocular surface disorders.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Mouse ocular surface potential difference (OSPD) measurements of LPARs modulators.
OSPD summarized tracings in WT-BALB/c mice treated with topical LPA (general LPARs agonist) with and without Ki 16425 (LPAR_1-3 antagonist) compared to 100µM ATP (Ca²⁺ agonist) (A). OSPD changes in mice treated with Alkyl-OMPT (LPAR_1/3/6 agonist), UCM-05104 (selective LPAR₁ agonist), 2S-OMPT (selective LPAR₃ agonist), and Alkyl-OMPT with Ki 16425 (selective LPAR₆ agonist) . **p<0.01, ***p<0.001.

 

Ocular surface LPAR₃ expression.
LPAR₃ immunofluorescence staining in mouse and human corneal and conjunctival epithelia.