Abstract
Abstract
Anion exchanger 4 (Ae4), encoded by solute carrier family 4 member 9 (Slc4a9), is required for normal salivary secretion, but how it supports fluid secretion remains poorly understood. Nearly a decade ago, we developed a mathematical model that attributed reduced secretion following Ae4 knockout primarily to Ae4 mediated monovalent cation transport.
Here, we reassess that interpretation by developing a dynamic model of salivary fluid secretion informed by subsequent experimental findings. The model incorporates
β
-adrenergic regulation of Ae4 and an additional apical chloride conductance shared by the control and knockout. To isolate the contribution of Ae4, the NKCC1 and Ae2 cycle rates calculated from the evolving control state are also prescribed in the knockout. Under these conditions, the knockout model secretes 20% less fluid over 600 s despite identical apical chloride conductances. The control begins with a larger intracellular chloride store and continues to acquire chloride through Ae4 during stimulation. The intracellular chloride difference increases during stimulation, whilst the weaker apical electrochemical driving force in the knockout reduces chloride export and fluid secretion. The analysis also identifies the alkalinity requirement of sustained Ae4 transport and quantifies the additional NKCC1 and Ae2 transport needed to compensate for its loss. These results support intracellular chloride availability as a mechanism linking Ae4 loss to reduced salivary secretion.