Zn(2+) stimulates salivary secretions via metabotropic zinc receptor ZnR/GPR39 in human salivary gland cells

Zn(2+) is a divalent cation that is essential for many biological activities, as it influences many ion channels and enzymatic activities. Zn(2+) can evoke G-protein-coupled receptor signaling via activation of the metabotropic zinc receptor ZnR/GPR39. In spite of evidence suggesting the presence of ZnR/GPR39 in salivary gland cells, there has been no evidence of ZnR/GPR39-mediated modulation of salivary gland function. Here we characterized the role of ZnR/GPR39 in human submandibular gland cells. A 0.25% ZnCl(2) solution evoked secretion of unstimulated and stimulated whole saliva in humans. We found that ZnR/GPR39 is expressed in human submandibular glands and HSG cells. Zn(2+) increased cytosolic Ca(2+) concentration ([Ca(2+)](i)) in a concentration-dependent manner. Muscarinic antagonist had no effect on Zn(2+)-induced [Ca(2+)](i) increase, which was completely blocked by the phospholipase C-β inhibitor. As with muscarinic agonist, Zn(2+) also induced the translocation of aquaporin-5 (AQP-5) to the plasma membrane, which was drastically decreased in ZnR/GPR39-knockdown cells. These data suggest that the metabotropic Zn(2+) receptor ZnR/GPR39 can modulate salivary secretion in human submandibular gland cells independent of muscarinic or histamine receptor signaling.