Figure 12. Scheme for anion transport by Calu-3 cells under the conditions used in this study.

In resting cells, an apical Ca²⁺ microdomain produced by store-operated Ca²⁺ entry causes partial activation of CFTR through stimulation of membrane-bound adenylyl cyclase and local elevation of [cAMP]. Secretagogues that further elevate [cAMP_i] stimulate apical Cl⁻ and HCO₃⁻ efflux, creating an acid load that may further increase CFTR open probability (Chen et al. 2009). Regulation of pH_i by HCO₃⁻ that enters via NBCe1 provides CO₂ for bicarbonate synthesis by carbonic anhydrase, which sustains HCO₃⁻ secretion. Most bicarbonate entering via NBCe1 is recycled basolaterally by anion exchange during Cl⁻ loading. Not shown in this scheme are other anion exchangers and Na⁺/H⁺ exchangers that are active under other conditions; i.e. Na⁺/H⁺ exchange is likely to mediate pH_i regulation during stimulation by secretagogues that hyperpolarize the basolateral membrane.