The Roles of Extracellular Calcium-Sensing Receptor (CaSR) in Ocular Surface Ion Transport

Abstract

Purpose : Various ion channels and transporters are implicated in ocular surface hydration, such as epithelial Na⁺ channel (ENaC), cystic fibrosis transmembrane conductance regulator (CFTR) Cl^- channel, and Ca²⁺-activated Cl^- channels (CaCCs). Extracellular calcium-sensing receptor (CaSR) is a G-protein-coupled receptor expressed in epithelial tissues across the body. Our group recently showed that CaSR is a regulator of ion transport in CFTR-expressing epithelial cells including gastrointestinal and airway epithelia. Here we investigate the role of CaSR in ocular surface epithelia.

Methods : We studied CaSR expression using immunostaining in mouse and human corneas and tested the effects of the CaSR agonist cinacalcet on mouse ocular surface ion transport using in vivo ocular surface potential difference (OSPD) measurements.

Results : CaSR is expressed in the corneal epithelium of mice and humans (Figure 1). Topically administered CaSR agonist cinacalcet has no effect on baseline OSPD or Na⁺ absorption mediated by ENaC, however, cinacalcet concentration-dependently inhibited cAMP agonist forskolin-induced Cl^- secretion and CFTR activity by up to 90% at 30 μM. Interestingly, cinacalcet treatment also largely inhibited Ca²⁺ agonist ATP-induced Cl^- secretion at 30 μM (Figure 2).

Conclusions : Our results suggest CaSR is an important regulator of ocular surface ion transport. Although dry eye is not among the commonly reported side effects of FDA-approved CaSR agonists such as cinacalcet, our findings suggest that CaSR agonist treatment may reduce ocular surface Cl^- secretion.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

Calcium-sensing receptor (CaSR) immunofluorescence staining in mouse (A) and human (B) corneas using a 1:200 dilution of mouse monoclonal anti-CaSR antibody.

 

Ocular surface potential difference (OSPD) measurement representative tracings (A), summarized tracings (B), and millivolt (mV) changes (C) in wild-type BALB/c mice treated with topical cinacalcet at various concentrations. ** p < 0.01, *** p < 0.001