The zinc-sensing receptor, ZnR/GPR39: Signaling and significance

The structural role of Zn²⁺ in stabilizing numerous enzymes and zinc fingers of transcription factors has been well established for several decades. Therefore, the major effects of this metal ion on growth, development, and cognitive function were not surprising. The importance of cellular homeostasis of Zn²⁺ is underlined by the identification of more than 20 proteins involved in transport of Zn²⁺ into the cytoplasm and various organelles. In the past decade, evidence for a signaling role of Zn²⁺ is emerging, suggesting this ion acts as a first and second messenger. Thus, transient changes in extracellular and intracellular Zn²⁺ were monitored and Zn²⁺-dependent regulation of multiple signaling pathways was shown. We have identified the function of ZnR, a Gq protein-coupled receptor that triggers the release of Ca²⁺ via the IP3 pathway. This ZnR-dependent signaling regulates cellular pathways involved in survival and proliferation, such as the MAP and PI3 kinase pathways, as well as modulation of ion transport systems such as the Na⁺/H⁺ exchanger or the K⁺/Cl^- co-transporter. The GPR39 was then shown to mediate extracellular Zn²⁺-dependent ZnR signaling. Here we discuss the major role of ZnR/GPR39 as the link between extracellular Zn²⁺ and intracellular signaling pathways regulating the physiological function of epithelial and neuronal cells. A major future challenge will be to identify the role of ZnR/GPR39 in diseases linked to Zn²⁺ dyshomeostasis.