Submitted on April 1, 2003
Accepted on June 26, 2003
A Critical Role for NHE1 in Intracellular pH Regulation in Pancreatic Acinar Cells
David A. Brown1, James E. Melvin2, and David I. Yule1*
1 Department of Pharmacology and Physiology, University of Rochester, Rochester, NY, USA
2 Center for Oral Biology, University of Rochester, Rochester, NY, USA
* To whom correspondence should be addressed. E-mail: David_Yule{at}urmc.rochester.edu.
The primary function of pancreatic acinar cells is to secrete digestive enzymes together with a NaCl-rich, primary fluid which is later greatly supplemented and modified by the pancreatic duct. Na+/H+ exchanger(s) (NHE) are proposed to be integral in the process of fluid secretion both in terms of the transcellular flux of Na+ and intracellular pH (pHi) regulation. Multiple NHE isoforms have been identified in pancreatic tissue, but little is known about their individual functions in acinar cells. The Na+/H+ exchange inhibitor 5-(N-ethyl-N-isopropyl) amiloride (EIPA) completely blocked the pHi recovery after an NH4Cl induced acid challenge, confirming a general role for NHE in pHi regulation. The targeted disruption of the Nhe1 gene also completely abolished pHi recovery from an acid load in pancreatic acini in both bicarbonate containing and bicarbonate-free solutions. In contrast, the disruption of either Nhe2 or Nhe3 had no effect on pHi recovery. In addition, NHE1 activity was up-regulated in response to muscarinic stimulation in wild-type, but not in NHE1 deficient mice. Fluctuations in pHi could potentially have major effects on calcium signaling following secretagogue stimulation, however the targeted disruption of Nhe1 was found to have no significant effect on intracellular calcium homeostasis. These data demonstrates that NHE1 is the major regulator of pHi in both resting and muscarinic agonist-stimulated pancreatic acinar cells.
