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] 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] 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.