Zn2+ stimulates salivary secretions via metabotropic zinc receptor ZnR/GPR39 in human salivary gland cells

Abstract

Zn2+ is a divalent cation that is essential for many biological activities, as it influences many ion channels and enzymatic activities. Zn2+ 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% ZnCl2 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. Zn2+ increased cytosolic Ca2+ concentration ([Ca2+]i) in a concentration-dependent manner. Muscarinic antagonist had no effect on Zn2+-induced [Ca2+]i increase, which was completely blocked by the phospholipase C-β inhibitor. As with muscarinic agonist, Zn2+ 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 Zn2+ receptor ZnR/GPR39 can modulate salivary secretion in human submandibular gland cells independent of muscarinic or histamine receptor signaling.

Oral Symptoms Associated with COVID-19 and Their Pathogenic Mechanisms: A Literature Review

“…Since human salivary glands express ACE2 and TMPRSS2, salivary gland infection with SARS-CoV-2 would affect saliva secretion, thereby altering the tasting ability. Zinc increases the secretion of unstimulated and stimulated whole saliva in humans [ 172 ]. Conversely, zinc deficiency associated with COVID-19 may induce gustatory dysfunction through hyposalivation.…”

“…Kim et al [ 172 ] collected unstimulated and stimulated whole saliva from patients with hyposalivation, Sjögren syndrome patients, and healthy subjects. Mouth rinsing with 0.25% ZnCl 2 solution increased both saliva in all groups, indicating that zinc stimulates saliva secretion.…”

The Zinc-Sensing Receptor GPR39 in Physiology and as a Pharmacological Target

“…Zn 2+ has been indicated to have a role in salivary secretion disorders and taste [ 154 ] and is found in the secretory granules of the salivary glands [ 155 ]. GPR39 signaling was shown to take place in ductal salivary gland cells (HSY) [ 24 , 27 ] and later in human submandibular glands and gland cells (HSGs) [ 156 ]. Recently, a ZnCl 2 solution was shown to trigger saliva secretion in humans and using human submandibular gland cells, Zn 2+ was shown to induce the intracellular Ca 2+ response and aquaporin-5 translocation to the plasma membrane [ 156 ], both in a key role in salivary secretion regulation [ 157 , 158 ].…”

“…GPR39 signaling was shown to take place in ductal salivary gland cells (HSY) [ 24 , 27 ] and later in human submandibular glands and gland cells (HSGs) [ 156 ]. Recently, a ZnCl 2 solution was shown to trigger saliva secretion in humans and using human submandibular gland cells, Zn 2+ was shown to induce the intracellular Ca 2+ response and aquaporin-5 translocation to the plasma membrane [ 156 ], both in a key role in salivary secretion regulation [ 157 , 158 ]. The effects were shown to be GPR39-mediated by their drastic reduction in GPR39 knockdown cells [ 156 ].…”

“…Recently, a ZnCl 2 solution was shown to trigger saliva secretion in humans and using human submandibular gland cells, Zn 2+ was shown to induce the intracellular Ca 2+ response and aquaporin-5 translocation to the plasma membrane [ 156 ], both in a key role in salivary secretion regulation [ 157 , 158 ]. The effects were shown to be GPR39-mediated by their drastic reduction in GPR39 knockdown cells [ 156 ]. GPR39 expression has also been reported in the sperm tail and the acrosome [ 159 , 160 ] and Zn 2+ -induced GPR39 activation was shown to stimulate sperm acrosomal exocytosis [ 160 ] and hyper-activated motility [ 159 ].…”