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

We develop a mathematical model of a salivary gland acinar cell with the objective of investigating the role of two [Formula: see text] 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 [Formula: see text] movement. Here, a basolateral [Formula: see text] adenosine triphosphatase pump (NaK-ATPase) and a [Formula: see text]-[Formula: see text]-[Formula: see text] cotransporter (Nkcc1) are primarily responsible for concentrating the intracellular space with [Formula: see text] well above its equilibrium potential. Gustatory and olfactory stimuli induce the release of [Formula: see text] ions from the internal stores of acinar cells, which triggers saliva secretion. [Formula: see text]-dependent [Formula: see text] and [Formula: see text] 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 [Formula: see text] anion exchangers (Ae), coupled with a basolateral [Formula: see text] ([Formula: see text]) (Nhe1) antiporter, regulate intracellular pH and act as a secondary [Formula: see text] uptake mechanism (Nauntofte in Am J Physiol Gastrointest Liver Physiol 263(6):G823-G837, 1992; Melvin et al. in Annu Rev Physiol 67:445-469, 2005. https://doi.org/10.1146/annurev.physiol.67.041703.084745 ). Recent studies demonstrated that Ae4 deficient mice exhibit an approximate [Formula: see text] decrease in gland salivation (Peña-Münzenmayer et al. in J Biol Chem 290(17):10677-10688, 2015). 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 [Formula: see text] 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.