Transepithelial bicarbonate secretion: lessons from the pancreas

Abstract

Many cystic fibrosis transmembrane conductance regulator (CFTR)-expressing epithelia secrete bicarbonate (HCO(3)(-))-containing fluids. Recent evidence suggests that defects in epithelial bicarbonate secretion are directly involved in the pathogenesis of cystic fibrosis, in particular by building up hyperviscous mucus in the ductal structures of the lung and pancreas. Pancreatic juice is one of the representative fluids that contain a very high concentration of bicarbonate among bodily fluids that are secreted from CFTR-expressing epithelia. We introduce up-to-date knowledge on the basic principles of transepithelial bicarbonate transport by showing the mechanisms involved in pancreatic bicarbonate secretion. The model of pancreatic bicarbonate secretion described herein may also apply to other exocrine epithelia. As a central regulator of bicarbonate transport at the apical membrane, CFTR plays an essential role in both direct and indirect bicarbonate secretion. The major role of CFTR in bicarbonate secretion would be variable depending on the tissue and cell type. For example, in epithelial cells that produce a low concentration of bicarbonate-containing fluid (up to 80 mm), either CFTR-dependent Cl(-)/HCO(3)(-) exchange or CFTR anion channel with low bicarbonate permeability would be sufficient to generate such fluid. However, in cells that secrete high-bicarbonate-containing fluids, a highly selective CFTR bicarbonate channel activity is required. Therefore, understanding the molecular mechanism of transepithelial bicarbonate transport and the role of CFTR in each specific epithelium will provide therapeutic strategies to recover from epithelial defects induced by hyposecretion of bicarbonate in cystic fibrosis.

Figure 1.

Ion transporters involved in transepithelial bicarbonate transport. Major transporters in the basolateral and luminal membranes of bicarbonate-secreting epithelial cells are illustrated. Bicarbonate uptake through the basolateral membrane is achieved by the NBCe1-B and the combinatorial function of NHE1 and CAs. Apical HCO₃⁻ secretion is mostly mediated by the CFTR anion channel and the Cl⁻/HCO₃⁻ exchanger Slc26a6 in pancreatic duct cells. Some epithelial cells also express (1) bicarbonate-reabsorbing mechanisms such as NHE3 and NBCn1-A; (2) ENaC, which mediates electrogenic Na⁺ absorption; and (3) K⁺ channels that secrete K⁺ to the luminal fluids in the apical membrane. Overall fluid secretion is driven by HCO₃⁻ secretion, and Na⁺ and water follow via a paracellular route. Water can also travel through a transcellular route via aquaporins.

Figure 2.

PDZ-based protein–protein interaction in bicarbonate-transporting epithelia. Many membrane receptors and transporters participating in the bicarbonate homeostasis in epithelial cells have a PDZ-binding motif (-X-T/S-X-hydrophobic amino acid) on their carboxyl terminus. The carboxy-terminal sequences are based on the human clones. Excluding purinergic receptors, most of the proteins are associated with cAMP-dependent processes. AC, Adenylyl cyclase; AKAP, cAMP-dependent protein kinase-anchoring protein; P2, purinergic receptor; RII, regulatory subunit of protein kinase A type II. (Other abbreviations are the same as described in the text.)

Figure 3.

A model of pancreatic fluid and bicarbonate secretion. In the proximal pancreatic duct, cAMP signals activate the CFTR-dependent Cl⁻/HCO₃⁻ exchange at the apical membrane, which enables the duct to absorb part of the Cl⁻ and secrete as much as 80–100 mm HCO₃⁻ along with a large volume of fluid into the pancreatic juice. As the fluid arrives at the more distal portions of the duct, the reduced luminal Cl⁻ and activated CFTR lower the intracellular Cl⁻ concentration [Cl⁻]_i to <10 mm. The low [Cl^-]_i activates WNK1, which phosphorylates SPAK/OSR1, which, in turn, acts on CFTR by converting it into a bicarbonate-selective channel. In contrast, the WNK1-SPAK/OSR1 pathway concurrently inhibits the function of apical Cl⁻/HCO₃⁻ exchange to prevent bicarbonate reabsorption.