The Zinc Sensing Receptor, ZnR/GPR39, in Health and Disease

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2018 Feb 2

PMID 29389900

Citations 47

Authors

Michal Hershfinkel

Affiliations

Soon will be listed here.

Abstract

A distinct G-protein coupled receptor that senses changes in extracellular Zn, ZnR/GPR39, was found in cells from tissues in which Zn plays a physiological role. Most prominently, ZnR/GPR39 activity was described in prostate cancer, skin keratinocytes, and colon epithelial cells, where zinc is essential for cell growth, wound closure, and barrier formation. ZnR/GPR39 activity was also described in neurons that are postsynaptic to vesicular Zn release. Activation of ZnR/GPR39 triggers Gαq-dependent signaling and subsequent cellular pathways associated with cell growth and survival. Furthermore, ZnR/GPR39 was shown to regulate the activity of ion transport mechanisms that are essential for the physiological function of epithelial and neuronal cells. Thus, ZnR/GPR39 provides a unique target for therapeutically modifying the actions of zinc in a specific and selective manner.

Citing Articles

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References

Han Y, Wu S . Modulation of glycine receptors in retinal ganglion cells by zinc. Proc Natl Acad Sci U S A. 1999; 96(6):3234-8. PMC: 15925. DOI: 10.1073/pnas.96.6.3234. View

Ishii K, Sato M, Akita M, Tomita H . Localization of zinc in the rat submandibular gland and the effect of its deficiency on salivary secretion. Ann Otol Rhinol Laryngol. 1999; 108(3):300-8. DOI: 10.1177/000348949910800315. View

Lu J, Karadsheh M, Delpire E . Developmental regulation of the neuronal-specific isoform of K-Cl cotransporter KCC2 in postnatal rat brains. J Neurobiol. 1999; 39(4):558-68. View

Barceloux D . Zinc. J Toxicol Clin Toxicol. 1999; 37(2):279-92. DOI: 10.1081/clt-100102426. View

Wildman S, King B, Burnstock G . Modulatory activity of extracellular H+ and Zn2+ on ATP-responses at rP2X1 and rP2X3 receptors. Br J Pharmacol. 1999; 128(2):486-92. PMC: 1571645. DOI: 10.1038/sj.bjp.0702802. View

Sandstead H, Frederickson C, Penland J . History of zinc as related to brain function. J Nutr. 2000; 130(2S Suppl):496S-502S. DOI: 10.1093/jn/130.2.496S. View

Acuna-Castillo C, Morales B, Huidobro-Toro J . Zinc and copper modulate differentially the P2X4 receptor. J Neurochem. 2000; 74(4):1529-37. DOI: 10.1046/j.1471-4159.2000.0741529.x. View

Cole T, Robbins C, Wenzel H, Schwartzkroin P, Palmiter R . Seizures and neuronal damage in mice lacking vesicular zinc. Epilepsy Res. 2000; 39(2):153-69. DOI: 10.1016/s0920-1211(99)00121-7. View

Macdonald R . The role of zinc in growth and cell proliferation. J Nutr. 2000; 130(5S Suppl):1500S-8S. DOI: 10.1093/jn/130.5.1500S. View

10.

Kim S, Jung Y, Kim D, Koh H, Chung J . Extracellular zinc activates p70 S6 kinase through the phosphatidylinositol 3-kinase signaling pathway. J Biol Chem. 2000; 275(34):25979-84. DOI: 10.1074/jbc.M001975200. View

11.

Taylor K . LIV-1 breast cancer protein belongs to new family of histidine-rich membrane proteins with potential to control intracellular Zn2+ homeostasis. IUBMB Life. 2000; 49(4):249-53. DOI: 10.1080/15216540050033087. View

12.

Bloc A, Cens T, Cruz H, Dunant Y . Zinc-induced changes in ionic currents of clonal rat pancreatic -cells: activation of ATP-sensitive K+ channels. J Physiol. 2000; 529 Pt 3:723-34. PMC: 2270222. DOI: 10.1111/j.1469-7793.2000.00723.x. View

13.

Nugent S, Kumar D, Rampton D, Evans D . Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs. Gut. 2001; 48(4):571-7. PMC: 1728243. DOI: 10.1136/gut.48.4.571. View

14.

Vaneckova I, Beskid S, Zicha J, Pacha J . Intracellular pH regulation in colonocytes of rat proximal colon. Biochim Biophys Acta. 2001; 1536(2-3):103-15. DOI: 10.1016/s0925-4439(01)00039-4. View

15.

Gu X, Yao H, Haddad G . Increased neuronal excitability and seizures in the Na(+)/H(+) exchanger null mutant mouse. Am J Physiol Cell Physiol. 2001; 281(2):C496-503. DOI: 10.1152/ajpcell.2001.281.2.C496. View

16.

Hershfinkel M, Moran A, Grossman N, Sekler I . A zinc-sensing receptor triggers the release of intracellular Ca2+ and regulates ion transport. Proc Natl Acad Sci U S A. 2001; 98(20):11749-54. PMC: 58801. DOI: 10.1073/pnas.201193398. View

17.

Jiang D, Sullivan P, Sensi S, Steward O, Weiss J . Zn(2+) induces permeability transition pore opening and release of pro-apoptotic peptides from neuronal mitochondria. J Biol Chem. 2001; 276(50):47524-9. DOI: 10.1074/jbc.M108834200. View

18.

Oh S, Park K, Kim J, Choi K . Differential modulation of zinc-stimulated p21(Cip/WAF1) and cyclin D1 induction by inhibition of PI3 kinase in HT-29 colorectal cancer cells. Exp Mol Med. 2002; 34(1):27-31. DOI: 10.1038/emm.2002.4. View

19.

Woo N, Lu J, England R, McClellan R, Dufour S, Mount D . Hyperexcitability and epilepsy associated with disruption of the mouse neuronal-specific K-Cl cotransporter gene. Hippocampus. 2002; 12(2):258-68. DOI: 10.1002/hipo.10014. View

20.

Sturniolo G, Fries W, Mazzon E, Di Leo V, Barollo M, DInca R . Effect of zinc supplementation on intestinal permeability in experimental colitis. J Lab Clin Med. 2002; 139(5):311-5. DOI: 10.1067/mlc.2002.123624. View