Involvement of sodium–glucose cotransporter-1 activities in maintaining oscillatory Cl− currents from mouse submandibular acinar cells.

In salivary acinar cells, cholinergic stimulation induces elevations of cytosolic [Ca2+]i to activate the apical exit of Cl− through TMEM16A Cl− channels, which acts as a driving force for fluid secretion. To sustain the Cl− secretion, [Cl−]i must be maintained to levels that are greater than the electrochemical equilibrium mainly by Na+-K+-2Cl− cotransporter-mediated Cl− entry in basolateral membrane. Glucose transporters carry glucose into the cytoplasm, enabling the cells to produce ATP to maintain Cl− and fluid secretion. Sodium–glucose cotransporter-1 is a glucose transporter highly expressed in acinar cells. The salivary flow is suppressed by the sodium–glucose cotransporter-1 inhibitor phlorizin. However, it remains elusive how sodium–glucose cotransporter-1 contributes to maintaining salivary fluid secretion. To examine if sodium–glucose cotransporter-1 activity is required for sustaining Cl− secretion to drive fluid secretion, we analyzed the Cl− currents activated by the cholinergic agonist, carbachol, in submandibular acinar cells while comparing the effect of phlorizin on the currents between the whole-cell patch and the gramicidin-perforated patch configurations. Phlorizin suppressed carbachol-induced oscillatory Cl− currents by reducing the Cl− efflux dependent on the Na+-K+-2Cl− cotransporter-mediated Cl− entry in addition to affecting TMEM16A activity. Our results suggest that the sodium–glucose cotransporter-1 activity is necessary for maintaining the oscillatory Cl− secretion supported by the Na+-K+-2Cl− cotransporter activity in real time to drive fluid secretion. The concerted effort of sodium–glucose cotransporter-1, Na+-K+-2Cl− cotransporter, and apically located Cl− channels might underlie the efficient driving of Cl− secretion in different secretory epithelia from a variety of animal species. [ABSTRACT FROM AUTHOR]