The zinc sensing receptor ZnR GPR39 in health and disease

Abstract

While zinc has had a well-established structural role for many years, it is only during the last two decades that its role as a signaling molecule has been recognized. Ionic zinc, Zn, that is endogenously released during physiological activity acts as a first messenger, triggering the activity of a distinct Zn-sensing-receptor, ZnR. The ZnR is a member of the Gq-coupled receptor family, and the molecular moiety mediating its activity is GPR39. In this review, we will discuss the role of the ZnR/GPR39 in mediating Zn-dependent signaling in epithelial tissues and in neurons, where Zn homeostasis plays physiological as well as pathological roles. Importantly, ZnR/GPR39 activates signaling that regulates a remarkably wide range of cell functions, including proliferation, differentiation and survival, as well as modulation of ion transport, and thereby, regulation of Na, H and Cl homeostasis. Moreover, signaling activated by ZnR/GPR39 plays a key role in mediating effects of Zn in health and disease. Thus, ZnR/GPR39 provides a unique target for therapeutically modifying the actions of zinc in a specific and selective manner.

Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth

“…We show that ZnR/GPR39 expression and function are increased in TAMR cells, compared to the original MCF-7 cells. Importantly, changes in intracellular Zn 2+ do not induce direct ZnR/GPR39 signaling 33 , 35 , but the higher levels of accumulated Zn 2+ 20 , 51 may suggest that transient extracellular changes by release of Zn 2+ 39 can trigger ZnR/GPR39 activation and enhanced cell growth. Importantly, ZnR/GPR39 is essential for Zn 2+ -dependent signaling leading to enhanced cell growth in the TAMR cells as well as in MDA-MB-453 cells and BT20 cells.…”

“…The release of vesicular Zn 2+ induces robust and transient rises in its local concentrations, followed by rapid re-uptake via ZIP transporters or chelation by Zn 2+ binding proteins 15 . Such transient changes in concentrations of extracellular Zn 2+ induce signaling via a Zn 2+ -sensing, G-protein coupled receptor, ZnR/GPR39 33 – 35 . The ZnR/GPR39 triggers intracellular Ca 2+ release and subsequently activates the mitogen activated protein kinase (MAPK) or PI3K/AKT pathways 36 – 38 .…”

GPR39 agonist TC-G 1008 promotes osteoblast differentiation and mineralization in MC3T3-E1 cells

“…GPR39 is a conserved orphan GPCR that has been shown to be involved in zinc ion transport as well as other aspects of metabolic regulation [8]. Recently, a new compound named TC-G 1008 (also named as GPR39-C3) was developed based on 2-pyridylpyrimidines and has been shown to be highly specific in binding to GPR39, making it a powerful tool to investigate the function of this receptor in diverse cell types [9,10].…”

Biogenesis of zinc storage granules inDrosophila melanogaster

“…As the Malpighian tubules are typically involved in excretion (Chi et al, 2015;Halberg et al, 2015;Yin et al, 2017), one intriguing possibility is that zinc storage granules provide a source of zinc for the intestinal lumen. In this view, the Malpighian tubule principal cells would have a similar physiological purpose as the intestinal paneth cells in mammals, where the secreted zinc has been implicated in the maintenance of the stem cell niche and epithelial integrity (Geiser et al, 2012;Ohashi et al, 2016;Podany et al, 2016;Sunuwar et al, 2016Sunuwar et al, , 2017aSunuwar et al, , 2017b. Another possibility is that luminal zinc may function as a regulator for intestinal microbiota and endosymbionts, or for the control of a commonly occurring natural pathogen (Brownlie et al, 2009;Bonfini et al, 2016;Mistry et al, 2016;Martino et al, 2017;Martinson et al, 2017;Clark and Walker, 2018).…”