A new role for bicarbonate in mucus formation

Abstract

The impact of small anions on the physical properties of gel-forming mucin has been almost overlooked relative to that of cations. Recently, based on the coincident abnormalities in HCO3−secretion and abnormal mucus formed in the hereditary disease cystic fibrosis (CF), HCO3−was hypothesized to be critical in the formation of normal mucus by virtue of its ability to sequester Ca2+from condensed mucins being discharged from cells. However, direct evidence of the impact of HCO3−on mucus properties is lacking. Herein, we demonstrate for the first time that mucin diffusivity (∼1/viscosity) increases as a function of [HCO3−]. Direct measurements of exocytosed mucin-swelling kinetics from airway cells showed that mucin diffusivity increases by ∼300% with 20 mM extracellular HCO3−concentration. Supporting data indicate that HCO3−reduces free Ca2+concentration and decreases the amount of Ca2+that remains associated with mucins. The results demonstrate that HCO3−enhances mucin swelling and hydration by reducing Ca2+cross-linking in mucins, thereby decreasing its viscosity and likely increasing its transportability. In addition, HCO3−can function as a Ca2+chelator like EGTA to disperse mucin aggregates. This study indicates that poor HCO3−availability in CF may explain why secreted mucus remains aggregated and more viscous in affected organs. These insights bear on not only the fundamental pathogenesis in CF, but also on the process of gel mucus formation and release in general.