Involvement of sodium-glucose cotransporter-1 activities in maintaining oscillatory Cl^- currents from mouse...

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.