A Mathematical Model Supports a Key Role for Ae4 (Slc4a9) in Salivary Gland Secretion

摘要

We develop a mathematical model of a salivary gland acinar cell with the objective of investigating the role of two Cl-/HCO3- exchangers from the solute carrier family 4 (Slc4), Ae2 (Slc4a2) and Ae4 (Slc4a9), in fluid secretion. Water transport in this type of cell is predominantly driven by Cl⁻ movement. Here, a basolateral Na⁺/K⁺ adenosine-triphosphatase pump (NaK-ATPase) and a Na⁺–K⁺–2Cl⁻ cotransporter (Nkcc1) are primarily responsible for concentrating the intracellular space with Cl⁻ well above its equilibrium potential. Gustatory and olfactory stimuli induce the release of Ca²⁺ ions from the internal stores of acinar cells, which triggers saliva secretion. Ca²⁺-dependent Cl⁻ and K⁺ channels promote ion secretion into the luminal space thus creating an osmotic gradient that promotes water movement in the secretory direction. The current model for saliva secretion proposes that Cl-/HCO3- anion exchangers (Ae), coupled with a basolateral Na⁺/proton (H⁺) (Nhe1) antiporter, regulate intracellular pH and act as a secondary Cl⁻ uptake mechanism (, ). Recent studies demonstrated that Ae4 deficient mice exhibit an approximate 30% decrease in gland salivation (). Surprisingly, the same study revealed that absence of Ae2 does not impair salivation, as previously suggested. These results seem to indicate that the Ae4 may be responsible for the majority of the secondary Cl⁻ uptake and thus a key mechanism for saliva secretion. Here, by using ‘in-silico’ Ae2 and Ae4 knockout simulations, we produced mathematical support for such controversial findings. Our results suggest that the exchanger’s cotransport of monovalent cations is likely to be important in establishing the osmotic gradient necessary for optimal transepithelial fluid movement.