Abstract
The onset of salivary gland fluid secretion in response to muscarinic stimulation 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 resting and secreting acinar cells. Mice with targeted disruptions of the Nhe1, Nhe2, and Nhe3 genes were used to investigate the contribution of these proteins to the stimulation-induced up-regulation of NHE activity in mouse parotid acinar cells. The lack of NHE1, but not NHE2 or NHE3, prevented intracellular pH recovery from an acid load in resting acinar cells, in acini stimulated to secrete with the muscarinic agonist carbachol, and in acini shrunken by hypertonic addition of sucrose. In HCO(3)(-)-containing solution, the rate of intracellular pH recovery from a muscarinic agonist-stimulated acid 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 muscarinic agonist-stimulated acinar cells and suggest that up-regulation of NHE1 activity has an important role in modulating saliva production in vivo.
Highlights
The initial response of salivary gland acinar cells to a fluid secretion stimulus is an acidification of the cytosol resulting from the efflux of HCO3Ϫ into the lumen and the generation of acid equivalents via metabolic pathways linked to increased membrane transporter activity (1–3)
To confirm the molecular identity of the Naϩ/Hϩ exchanger activity in salivary gland acinar cells, we studied the functional consequences of disrupting the murine Nhe1, Nhe2, and Nhe3 genes on intracellular pH regulation in this cell type
Muscarinic stimulation produces copious amounts of parotid saliva, equivalent to ϳ5% of the whole body water content/h in mice (41). This vigorous rate of secretion is associated with a dramatic up-regulation of Naϩ/Hϩ exchanger activity, which alkalinizes the cytoplasm of salivary gland acinar cells (1–3)
Summary
The initial response of salivary gland acinar cells to a fluid secretion stimulus is an acidification of the cytosol resulting from the efflux of HCO3Ϫ into the lumen and the generation of acid equivalents via metabolic pathways linked to increased membrane transporter activity (1–3). The subcellular distribution of NHE2 and NHE3 appears to be species- and glandspecific (22, 24, 25) In addition to these uncertainties concerning isoform localization, very little is known about the specific functions of the individual NHE isoforms in acinar cells during resting conditions or when stimulated to secrete fluid. To confirm the molecular identity of the Naϩ/Hϩ exchanger activity in salivary gland acinar cells, we studied the functional consequences of disrupting the murine Nhe, Nhe, and Nhe genes on intracellular pH regulation in this cell type. Our results demonstrate that activation of the Naϩ/Hϩ exchanger isoform NHE1 is responsible for the upregulation observed during muscarinic stimulation and is the major regulator of intracellular pH in both resting and secreting cells.
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