Proton Pump Inhibitors Inhibit Pancreatic Secretion: Role of Gastric and Non-Gastric H.sup.+/K.sup.+-ATPases
Author(s): Jing Wang, Dagne Barbuskaite, Marco Tozzi, Andrea Giannuzzo, Christiane E. Sørensen, Ivana Novak *
Digestive processes along the gastrointestinal tract are aided by acidic and basic secretions by a number of epithelia. In particular, the pancreas and the stomach are the most avid base (HCO3 - ) and acid (H+ ) secretors, respectively. The gastric H+ secretory mechanisms are well established, however, the cellular mechanism by which pancreatic duct cells secrete almost isotonic HCO3 - fluid has long been a challenge to epithelial physiologists.
The current ion transport model for pancreatic HCO3 - secretor, the duct cell, involves two machineries on the two epithelial membranes: first, cells accumulate cellular HCO3 - with the help of a basolateral Na+ -HCO3 - cotransporter (pNBC, NBCe1) and a Na+ /H+ exchanger (NHE1) together with carbonic anhydrase; second, HCO3 - efflux occurs via co-operation between Cl- channels and Cl- /HCO3 - anion exchangers from the SLC26A6 family, e.g. SLC26A6 on the luminal membrane . The Cl- channels are the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels, which may have some HCO3 - permeability [2,3] and the Ca2+ -activated Cl- channels, such as TMEM16A/ANO1 . Furthermore, K+ channels (e.g. KCa 3.1, KCa 1.1, KCNQ1) maintain the membrane potential and provide the driving force for anion secretion together with the Na+ /K+ -ATPase [5-7]. Na+ and water follows passively. Nevertheless, this model can only explain production of 80-100 mM NaHCO3 in secreted fluid, yet human pancreas can secrete up to 140 mM NaHCO 3 . In addition to NBCs and NHE, earlier studies have shown vacuolar H + ATPase (V-ATPase) activity on the basolateral membrane of pancreatic ducts by intracellular pH (pHi ) measurements and use of the V-ATPase inhibitor bafilomycin A1 [8-11] Nevertheless, whether the V-ATPase plays a significant role in pancreatic HCO3 - secretion is not clarified, as for example in guinea pig pancreatic ducts bafilomycin A1 could not inhibit agonist-stimulated HCO3 - and fluid secretion [12,13]. Therefore, in the present study we have focused on the function of H+ /K+ -ATPases (pumps), which are pharmacologically approachable and physiologically relevant. Such H+ /K+ -pumps have not been proposed for HCO3 - secreting tissues, except for our earlier study on rat pancreatic ducts ; rather they have well-established roles in acid secretion, and in H + and K+ homeostasis in other tissues.
The H+ /K+ -ATPases are classified into two subfamilies, gastric and non-gastric (latter also called colonic), coded by ATP4A and ATP12A . The gastric H+ /K+ -ATPase is expressed in stomach parietal cells, kidney distal nephrons [15-17] and cochlea [18,19], where they are responsible for H+ secretion, K+ absorption and K+ recirculation, respectively. The non-gastric H+ /K+ -ATPase is present in several epithelial tissues including colon, kidney, skin, placenta, and prostate, and here it is associated with acid-base or K...
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