A Mathematical Model of the Pancreatic Duct Cell Generating High Bicarbonate Concentrations in Pancreatic Juice

Abstract

A simple CFTR-dependent duct cell model can explain active, high-volume, high-concentration bicarbonate secretion in pancreatic juice that reproduces the experimental findings. This model may also provide insight into why CFTR mutations that predominantly affect bicarbonate permeability predispose to pancreatic dysfunction in humans.

Cystic Fibrosis: Does CFTR Malfunction Alter pH Regulation?

“…During secretion the intracellular chloride concentration becomes so low that chloride secretion cannot be maintained and all the secretion is bicarbonate. This model was developed by many people [18] but was put to an elegant test in a paper by Whitcomb & Ermentrout [19] where they mathematically modeled the ductal secretion with predicted results that aligned exactly with those found by organ studies. The controversy in this field is simply explained as whether another protein, an apical chloride-bicarbonate exchanger, exists or is needed to produce the very high bicarbonate concentrations detected.…”

Transepithelial Bicarbonate Secretion: Lessons from the Pancreas

“…The Na þ gradient is used for cytosolic bicarbonate accumulation by Na þ -HCO 3 2 cotransporters (NBCs) and Na þ /H þ exchangers (NHEs) in the basolateral membrane, and the negative membrane potential facilitates bicarbonate efflux via the electrogenic anion channels and transporters in the apical membrane. (Ishiguro et al 1996a;Sohma et al 2000;Whitcomb and Ermentrout 2004). In addition, inhibitors of NHE1 and the V-type H þ -ATPase pump produced no or variable effects in reducing pancreatic bicarbonate secretion (Lee and Muallem 2008).…”

“…For example, the major basolateral bicarbonate influx mechanism was identified as NBCe1-B, which functions as a 1 Na þ /2 HCO 3 2 cotransporter (Zhao et al 1994;Ishiguro et al 1996a;Abuladze et al 1998). In addition, studies in perfused guinea pig pancreatic ducts and mathematical modeling suggested that a bicarbonate channel activity is required to set the final bicarbonate concentration in the pancreatic juice to 140 mM (Sohma et al 2000;Whitcomb and Ermentrout 2004).…”

“…Having a bicarbonate-selective channel in the apical membrane of a duct cell makes it theoretically possible to secrete up to 200 mM HCO 3 2 if cells maintain a membrane potential of 260 mV. It has been previously suggested that CFTR functions as a bicarbonate channel in pancreatic duct cells under some specific conditions (O'Reilly et al 2000;Reddy and Quinton 2003;Shcheynikov et al 2004;Whitcomb and Ermentrout 2004;Ishiguro et al 2009). However, the P HCO3 / P Cl of CFTR was reported to be 0.…”

“…Therefore, although basolateral AE2 is required for a housekeeping function of cells preventing overt intracellular alkalinization, its activation would inhibit apical bicarbonate secretion in epithelial cells. In fact, mathematical models suggest that inhibition of basolateral AE activity is required for the high bicarbonate secretion in pancreatic duct cells (Sohma et al 1996(Sohma et al , 2000Whitcomb and Ermentrout 2004).…”