Zinc in specialized secretory tissues: roles in the pancreas, prostate, and mammary gland

Abstract

Zinc (Zn) is an essential micronutrient required for over 300 different cellular processes, including DNA and protein synthesis, enzyme activity, and intracellular signaling. Cellular Zn homeostasis necessitates the compartmentalization of Zn into intracellular organelles, which is tightly regulated through the integration of Zn transporting mechanisms. The pancreas, prostate, and mammary gland are secretory tissues that have unusual Zn requirements and thus must tightly regulate Zn metabolism through integrating Zn import, sequestration, and export mechanisms. Recent findings indicate that these tissues utilize Zn for basic cellular processes but also require Zn for unique cellular needs. In addition, abundant Zn is transported into the secretory pathway and a large amount is subsequently secreted in a tightly regulated manner for unique biological processes. Expression of numerous members of the SLC30A (ZnT) and SLC39A (Zip) gene families has been documented in these tissues, yet there is limited understanding of their precise functional role in Zn metabolism or their regulation. Impairments in Zn secretion from the pancreas, prostate, and mammary gland are associated with disorders such as diabetes, infertility, and cancer, respectively. In this review, we will provide a brief summary of the specific role of Zn in each tissue and describe our current knowledge regarding how Zn metabolism is regulated. Finally, in each instance, we will reflect upon how this information shapes our current understanding of the role of Zn in these secretory tissues with respect to human health and disease.

Figure 1

Zn transport in various pancreatic cell types. (A) Localization of Zip1, Zip10, and Zip14 to pancreatic α-cells suggests that these transporters are responsible for importing Zn into the cell. Zn binds to and opens ATP dependent K(+) channels, allowing the efflux of Zn from the α-cell and inactivation of voltage dependent calcium channels, resulting in decreased glucagon secretion. (B) Zn is transported into pancreatic β-cell cells via Zip4. ZnT8 is responsible for the transport of Zn into insulin granules. Autoantibodies to ZnT8 and polymorphisms of ZnT8 are associated with the onset of DM. (C) Zip5 is responsible for the transport of Zn into pancreatic acinar cells. Zn is transported into zymogen granules by ZnT2 where it binds to and activates digestive enzymes that are subsequently secreted.

Figure 2

Zn transporter expression in the secreting epithelium of the rat prostate. Lobes of the rat prostate are illustrated on the left. On the right, a cartoon of an epithelial cell of the lateral lobe illustrates our current understanding of Zn transporter localization and Zn function. Zip2 and Zip3 are localized to the apical membrane and Zip1 is localized to the basal membrane; all function to import Zn into the cell. ZnT4, ZnT6, and ZnT7 are localized to the Golgi apparatus and ZnT2 is localized to the ER; these transporters likely function to maintain the secretory pathway. There is no known transporter for the mitochondria where high Zn levels inhibit the oxidation of citrate, providing a source for secretion.

Figure 3

Zn and Zn transporters involved in mammary gland function. Mammary gland is comprised of a network of branched ductal structures terminating at acinar units, also known as lobules. These structures are lined with MEC responsible for the production and secretion of milk into the collecting ducts for the developing neonate. (A) Although only localization of Zip3 and ZnT2 has been clearly established in normal/nonlactating tissue, ZnT4 is also known to be expressed. Zip6 and Zip7 are expressed in breast cells; however, their role in normal mammary gland is unknown. (B) During lactation, ZnT2 plays a major role in the secretion of Zn into milk, while Zip3 plays a role in the reuptake of Zn from the lumen. The localization and contribution of other Zn transporters during MEC differentiation and lactation remains to be determined and is an important question. (C) Hyper-accumulation of Zn has been associated with breast cancer. A limited number of Zn transporters (Zip5, Zip6, Zip7, Zip8, and Zip10) and MT have been shown to be overexpressed in this disease. However, their specific contribution to this phenotype and in MEC is remains to be delineated.