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 [Ca 2+ ] 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.