Acid-base transport in pancreas-new challenges

Abstract

Along the gastrointestinal tract a number of epithelia contribute with acid or basic secretions in order to aid digestive processes. The stomach and pancreas are the most extreme examples of acid (H(+)) and base (HCO(-) 3) transporters, respectively. Nevertheless, they share the same challenges of transporting acid and bases across epithelia and effectively regulating their intracellular pH. In this review, we will make use of comparative physiology to enlighten the cellular mechanisms of pancreatic HCO(-) 3 and fluid secretion, which is still challenging physiologists. Some of the novel transporters to consider in pancreas are the proton pumps (H(+)-K(+)-ATPases), as well as the calcium-activated K(+) and Cl(-) channels, such as KCa3.1 and TMEM16A/ANO1. Local regulators, such as purinergic signaling, fine-tune, and coordinate pancreatic secretion. Lastly, we speculate whether dys-regulation of acid-base transport contributes to pancreatic diseases including cystic fibrosis, pancreatitis, and cancer.

Keywords: ANO1; H+-K+-ATPase; IK; KCa3.1; TMEM16A; bicarbonate transport; pancreatic duct; proton transport.

Figure 1

HCO⁻₃ and H⁺ transport in gastric cells (A) and pancreatic duct cells (B). The models show schematically different types of epithelia as single cells. The transport of H⁺ or HCO⁻₃ to the bulk luminal fluid is shown with large arrows. The small arrows on luminal side indicate HCO⁻₃ and H⁺ secretions to the mucosal buffer zone. Flux of HCO⁻₃ and H⁺ to the interstititum/blood side indicates expected alkaline or acid tides.

Figure 2

Acid/base transport in pancreas. (A) The relation between secretory rates and HCO⁻₃ concentrations in pancreatic juice of various species. Secretions were stimulated by secretin and secretory rates were corrected for body weights. (B) The model of ion transport in a secreting pancreatic duct cell with novel transporters, channels and luminal purinergic signaling and receptors indicated in color and discussed in the review. Intracellular HCO⁻₃ is derived from CO₂ through the action of carbonic anhydrase (CA) and from HCO⁻₃ uptake via the electrogenic Na⁺–HCO⁻₃ cotransporter (pNBC, NBCe1). H⁺ is extruded at basolateral membrane by the Na⁺/H⁺ exchanger (NHE1). HCO⁻₃ efflux across the luminal membrane is mediated by the electrogenic Cl⁻/HCO⁻₃ exchanger (SLC26A6), and under certain conditions, through Cl⁻ channels. The luminal Cl⁻ channels are CFTR and TMEM16A (see text). There are a number of K⁺ channels expressed on the luminal and basolateral membranes, e.g., K_Ca3.1, K_Ca1.1, KCNQ1 (see text). The luminal and basolateral H⁺-K⁺-ATPases are indicated in red and green, and supposedly contribute to the luminal buffer zone and the H⁺ efflux to intersititum, respectively. Other ion channels and transporters, such as NHE3, SLC26A3, NBC3, NKCC1, and aquaporins have a differential distribution in the duct tree and for simplicity are not included in the model. (C) Immunolocalization of the gastric (red) and non-gastric (green) H⁺-K⁺ pumps in rat pancreatic duct. The bar is 20 μm. Modified from Novak et al., .