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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-? 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.

SUBMITTER: Kim YJ

PROVIDER: S-EPMC6881433 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Kim Yoon-Jung YJ Jo Youhwa Y Lee Yeon-Hee YH Park Kyungpyo K Park Hee-Kyung HK Choi Se-Young SY

Scientific reports 20191127 1

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 subma ...[more]

PMID: 31776425

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Project description:BackgroundPSMA-targeted radionuclide therapy (TRT) is a promising treatment for prostate cancer (PCa), but dose-limiting xerostomia can severely limit its clinical adaptation, especially when using alpha-emitting radionuclides. With [18F]DCFPyL as a surrogate for PSMA-TRT, we report a novel method to selectively reduce salivary gland (SG) uptake of systemically administered [18F]DCFPyL by immediate prior infusion of non-radioactive standard of [18F]DCFPyL (DCFPyL) directly into the SG via retrograde cannulation.MethodsA dose-finding cohort using athymic nude mice demonstrated proof of principle that SG uptake can be selectively blocked by DCFPyL administered either locally via cannulation (CAN group) or systemically (SYS group). The experiments were repeated in a validation cohort of 22RV1 tumor-bearing mice. Submandibular glands (SMG) of CAN mice were locally blocked with either saline or DCFPyL (dose range: 0.01× to 1000× molar equivalent of the radioactive [18F]DCFPyL dose). The radioactive dose of [18F]DCFPyL was administered systemically 10 min later and the mice euthanized after 1 h for biodistribution studies. Toxicity studies were done at up to 1000× dose.ResultsIn the dose-finding cohort, the SYS group showed a dose-dependent 12-40% decrease in both the SMG T/B and the kidney (tumor surrogate). Mild blocking was observed at 0.01× , with maximal blocking reached at 1× with no additional blocking up to 1000× . In the CAN group, blocking at the 0.1× and 1× dose levels resulted in a similar 42-53% decrease, but without the corresponding decrease in kidney uptake as seen in the SYS group. Some evidence of "leakage" of DCFPyL from the salivary gland into the systemic circulation was observed. However, experiments in 22RV1 tumor-bearing mice at the 0.1× and 1× dose levels confirm that, at the appropriate blocking dose, SG uptake of [18F]DCFPyL can be selectively reduced without affecting tumor uptake and with no toxicity.ConclusionOur results suggest that direct retrograde instillation of DCFPyL into the SG could predictably and selectively decrease salivary uptake of systemically administered [18F]DCFPyL without altering tumor uptake, if given at the appropriate dose. This novel approach is easily translatable to clinical practice and has the potential to mitigate xerostomia, without compromising the therapeutic efficacy of the PSMA-TRT.

Dataset Information

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

Publications

Zn<sup>2+</sup> stimulates salivary secretions via metabotropic zinc receptor ZnR/GPR39 in human salivary gland cells.

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