CFTR-regulated chloride transport at the ocular surface in living mice measured by potential differences

PURPOSE. To define the role of the cystic fibrosis transmembrane conductance regulator (CFTR) in Cl- secretion at the mouse ocular surface in vivo. METHODS. Open-circuit potential differences (PDs) across the fluid-bathed ocular surface were measured in anesthetized wild-type and cystic fibrosis (CF) mice in response to Cl- ion substitution and transport agonists and inhibitors. RESULTS. Basal ocular surface PD was -23 +/- 1 mV (SE; 20 wild-type mice), depolarizing to -16 +/- 2 mV after amiloride, then hyperpolarizing to -34 +/- 3 mV after low Cl-. CFTR activation by forskolin or a selective activator caused further sustained hyperpolarization to -50 to +/- 60 mV. UTP produced a comparable but transient hyperpolarization. The CFTR inhibitors CFTRinh-172 and GlyH-101 largely reversed agonist- but not low Cl--induced hyperpolarizations. PD in CF mice hyperpolarized by 2.1 mV after low Cl- and was insensitive to CFTR activators or inhibitors. CONCLUSIONS. CFTR provides a major pathway for mouse ocular surface Cl- secretion, suggesting the application of CFTR activators as therapy for dry eye. Amiloride-sensitive Na+ transporters facilitate Na+ absorption. PD measurements provide a robust and reproducible means of assessing ocular surface ion transporting mechanisms.