{"title":"Involvement of sodium–glucose cotransporter-1 activities in maintaining oscillatory Cl− currents from mouse submandibular acinar cells","authors":"","doi":"10.1007/s00360-024-01532-w","DOIUrl":null,"url":null,"abstract":"<h3>Abstract</h3> <p>In salivary acinar cells, cholinergic stimulation induces elevations of cytosolic [Ca<sup>2+</sup>]<sub>i</sub> to activate the apical exit of Cl<sup>−</sup> through TMEM16A Cl<sup>−</sup> channels, which acts as a driving force for fluid secretion. To sustain the Cl<sup>−</sup> secretion, [Cl<sup>−</sup>]<sub>i</sub> must be maintained to levels that are greater than the electrochemical equilibrium mainly by Na<sup>+</sup>-K<sup>+</sup>-2Cl<sup>−</sup> cotransporter-mediated Cl<sup>−</sup> entry in basolateral membrane. Glucose transporters carry glucose into the cytoplasm, enabling the cells to produce ATP to maintain Cl<sup>−</sup> 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<sup>−</sup> secretion to drive fluid secretion, we analyzed the Cl<sup>−</sup> 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<sup>−</sup> currents by reducing the Cl<sup>−</sup> efflux dependent on the Na<sup>+</sup>-K<sup>+</sup>-2Cl<sup>−</sup> cotransporter-mediated Cl<sup>−</sup> entry in addition to affecting TMEM16A activity. Our results suggest that the sodium–glucose cotransporter-1 activity is necessary for maintaining the oscillatory Cl<sup>−</sup> secretion supported by the Na<sup>+</sup>-K<sup>+</sup>-2Cl<sup>−</sup> cotransporter activity in real time to drive fluid secretion. The concerted effort of sodium–glucose cotransporter-1, Na<sup>+</sup>-K<sup>+</sup>-2Cl<sup>−</sup> cotransporter, and apically located Cl<sup>−</sup> channels might underlie the efficient driving of Cl<sup>−</sup> secretion in different secretory epithelia from a variety of animal species.</p>","PeriodicalId":15377,"journal":{"name":"Journal of Comparative Physiology B","volume":"2 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Comparative Physiology B","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1007/s00360-024-01532-w","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
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Abstract
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.
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