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HORMONES AND SIGNALING

Critical role for NHE1 in intracellular pH regulation in pancreatic acinar cells

¹Department of Pharmacology and Physiology and ²Center for Oral Biology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York 14642

Submitted 1 April 2003 ; accepted in final form 26 June 2003

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 (pH_i) 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 pH_i recovery after an NH₄Cl-induced acid challenge, confirming a general role for NHE in pH_i regulation. The targeted disruption of the Nhe1 gene also completely abolished pH_i recovery from an acid load in pancreatic acini in both -containing and -free solutions. In contrast, the disruption of either Nhe2 or Nhe3 had no effect on pH_i recovery. In addition, NHE1 activity was upregulated in response to muscarinic stimulation in wild-type mice but not in NHE1-deficient mice. Fluctuations in pH_i 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 pH_i in both resting and muscarinic agonist-stimulated pancreatic acinar cells.

fluid secretion; exocrine glands; intracellular pH regulation; intracellular calcium

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