Critical role for NHE1 in intracellular pH regulation in pancreatic acinar cells.
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. A Na+/H+ exchanger(s) [NHE(s)] is 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 completely blocked 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 HCO3--containing and HCO3--free solutions. In contrast, the disruption of either Nhe2 or Nhe3 had no effect on pHi recovery. In addition, NHE1 activity was upregulated in response to muscarinic stimulation in wild-type mice but not in NHE1-deficient mice. Fluctuations in pHi could potentially have major effects on Ca2+ signaling following secretagogue stimulation; however, the targeted disruption of Nhe1 was found to have no significant effect on intracellular Ca2+ homeostasis. These data demonstrate that NHE1 is the major regulator of pHi in both resting and muscarinic agonist-stimulated pancreatic acinar cells.
Brown
David A
DA
Dept. of Pharmacology and Physiology, School of Medicine and Dentistry, Univ. of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USA. david_yule@urmc.rochester.edu
Melvin
James E
JE
Yule
David I
DI
D000143:Acids / Q000378:metabolism; D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D002021:Buffers; D020013:Calcium Signaling; D002217:Carbachol / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D007425:Intracellular Membranes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D010179:Pancreas / Q000378:metabolism*; D011522:Protons; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D000143:Acids; D001639:Bicarbonates; D002021:Buffers; D018721:Muscarinic Agonists; D011522:Protons; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D000584:Amiloride; D002217:Carbachol; C039614:ethylisopropylamiloride