The zinc sensing receptor, ZnR/GPR39, in health and disease

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, Zn²⁺, that is endogenously released during physiological activity acts as a first messenger, triggering the activity of a distinct Zn²⁺-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 Zn²⁺-dependent signaling in epithelial tissues and in neurons, where Zn²⁺ 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 Zn²⁺ in health and disease. Thus, ZnR/GPR39 provides a unique target for therapeutically modifying the actions of zinc in a specific and selective manner.