Targeted disruption of the NHE1 gene prevents muscarinic agonist-induced up-regulation of Na+/H+ exchange in mouse parotid acinar cells

The onset of salivary gland fluid secretion in response to muscarinic stimu lation is accompanied by up-regulation of Na+/H+ exchanger (NHE) activity. Although multiple NHE isoforms (NHE1, NHE2, and NHE3) have been identified in salivary glands, little is known about their specific function(s) in res ting and secreting acinar cells. Mice with targeted disruptions of the Nhe1 , Nhe2, and Nhe3 genes were used to investigate the contribution of these p roteins to the stimulation-induced up-regulation of NHE activity in mouse p arotid acinar cells. The lack of NHE1, but not NHE2 or NHE3, prevented intr acellular pH recovery from an acid load in resting acinar cells, in acini s timulated to secrete with the muscarinic agonist carbachol, and in acini sh runken by hypertonic addition of sucrose, In HCO3--containing solution, the rate of intracellular pH recovery from a muscarinic agonist-stimulated aci d load was significantly inhibited in acinar cells from mice lacking NHE1, but not in cells from NHE2- or NHE3-deficient mice. These data demonstrate that NHE1 is the major regulator of intracellular pH in both resting and mu scarinic agonist-stimulated acinar cells and suggest that up-regulation of NHE1 activity has an important role in modulating saliva production in vivo .