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Am J Physiol Cell Physiol 2018[Apr]; 314 (4): C404-C414 PMID29351417show ga
Zn(2+) is an essential element for cell survival/growth, and its deficiency is linked to many disorders. Extracellular Zn(2+) concentration changes participate in modulating fundamental cellular processes such as proliferation, secretion, ion transport, and cell signal transduction in a mechanism that is not well understood. Here, we hypothesize that the Zn(2+)-sensing receptor ZnR/G protein-coupled receptor 39 (GPR39), found in tissues where dynamic Zn(2+) homeostasis takes place, enables extracellular Zn(2+) to trigger intracellular signaling pathways regulating key cell functions in vascular cells. Thus, we investigated how extracellular Zn(2+) regulates cell viability, proliferation, motility, angiogenesis, vascular tone, and inflammation through ZnR/GPR39 in endothelial cells. Knockdown of GPR39 through siRNA largely abolished Zn(2+)-triggered cellular activity changes, Ca(2+) responses, as well as the downstream activation of Galphaq-PLC pathways. Extracellular Zn(2+) promoted vascular cell survival/growth through activation of cAMP and Akt as well as overexpressing of platelet-derived growth factor-alpha receptor and vascular endothelial growth factor A. It also enhanced cell adhesion and mobility, endothelial tubule formation, and cytoskeletal reorganization. Such effects from extracellular Zn(2+) were not observed in GPR39(-/-) endothelial cells. Zn(2+) also regulated inflammation-related key molecules such as heme oxygenase-1, selectin L, IL-10, and platelet endothelial cell adhesion molecule 1, as well as vascular tone-related prostaglandin I2 synthase and nitric oxide synthase-3. In sum, extracellular Zn(2+) regulates endothelial cell activity in a ZnR/GPR39-dependent manner and through the downstream G(alpha)q-PLC pathways. Thus, ZnR/GPR39 may be a therapeutic target for regulating endothelial activity.
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Am+J+Physiol+Cell+Physiol 2018 ; 314 (4): C404-C414
