The Role of ZnR/GPR39 in Regulation of Na⁺/K⁺ ATPase in Salivary Gland Cells

Introduction:Zn²⁺ is selectively concentrated in the secretory granules of the salivary glands. Interestingly, symptoms of zinc deficiency include a loss of taste sensation and reduced saliva secretion(dry mouth).How zinc regulates these functions is not well understood.In the salivary duct cell line,HSY, extracellular Zn²⁺ activates a Zn²⁺-sensing receptor, ZnR/GPR39.This receptor is a G-protein coupled receptor that triggers intracellular Ca²⁺ release and the subsequent regulation of signaling that is associated with epithelial functions. However, the link between ZnR/GPR39 and salivary function is not well understood.

Aim:We hypothesize that ZnR/GPR39 controls salivary gland function via the activation of Ca²⁺ signaling and the subsequent regulation of epithelial solute transport by the Na⁺/K⁺ ATPase pump. This transporter is present on the basolateral plasma membrane of salivary epithelial cells and regulates intracellular solute concentration.

Results:We found that Zn²⁺ enhances ion transport activity that is reduced in the presence of the inhibitor of the pump, ouabain. Similarly, the silencing of Na⁺/K⁺ ATPase using siRNA constructs abolished the enhanced ion transporter activity. Moreover, we monitored the Zn²⁺-dependent increase in K⁺ transport activity in acute slices of salivary parotid glands that were reduced by ouabain. In contrast, in ZnR/GPR39 knockout tissues, this activity was abolished, indicating that Zn²⁺ via ZnR/GPR39 regulates Na⁺/K⁺ ATPase activity.Finally, we found that salivary ion composition was disrupted in ZnR/GPR39 knockout mice, with the increased concentration of Na⁺ and K⁺ in the saliva.

Conclusion:Our results suggest that, in salivary gland cells, ZnR/GPR39 activates Na⁺/K⁺ ATPase activity, regulating ion gradient and saliva composition.