Cl-/HCO3-exchange is acetazolamide sensitive and activated by a muscarinic receptor-induced [Ca2+]iincrease in salivary acinar cells

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Abstract
Large volumes of saliva are generated by transepithelial Cl- movement during parasympathetic muscarinic receptor stimulation. To gain further insight into a major Cl- uptake mechanism involved in this process, we have characterized the anion exchanger (AE) activity in mouse serous parotid and mucous sublingual salivary gland acinar cells. The AE activity in acinar cells was Na+ independent, electroneutral, and sensitive to the anion exchange inhibitor DIDS, properties consistent with the AE members of the SLC4A gene family. Localization studies using a specific antibody to the ubiquitously expressed AE2 isoform labeled acini in both parotid and sublingual glands. Western blot analysis detected an ∼170-kDa protein that was more highly expressed in the plasma membranes of sublingual than in parotid glands. Correspondingly, the DIDS-sensitive exchanger activity was significantly greater in sublingual acinar cells. The carbonic anhydrase antagonist acetazolamide markedly inhibited, whereas muscarinic receptor stimulation enhanced, the exchanger activity in acinar cells from both glands. Intracellular Ca2+ chelation prevented muscarinic receptor-induced upregulation of the AE, whereas raising the intracellular Ca2+ concentration with the Ca2+-ATPase inhibitor thapsigargin mimicked the effects of muscarinic receptor stimulation. In summary, carbonic anhydrase activity was essential for regulating exchange in salivary gland acinar cells. Moreover, muscarinic receptor stimulation enhanced AE activity through a Ca2+-dependent mechanism. Such forms of regulation may play important roles in modulating fluid and electrolyte secretion by salivary gland acinar cells.