From Endoplasmic Reticulum to Secretory Granules: Role of Zinc in the Secretory Pathway of Growth Hormone

Abstract

Endocrine and neuroendocrine cells differ from cells which rapidly release all their secreted proteins in that they store some secretory proteins in concentrated forms in secretory granules to be rapidly released when cells are stimulated. Protein aggregation is considered as the first step in the secretory granule biosynthesis and, at least in the case of prolactin and growth hormone, greatly depends on zinc ions that facilitate this process. Hence, regulation of cellular zinc transport especially that within the regulated secretory pathway is of importance to understand. Various zinc transporters of Slc30a/ZnT and Slc39a/Zip families have been reported to fulfil this role and to participate in fine tuning of zinc transport in and out of the endoplasmic reticulum, Golgi complex and secretory granules, the main cellular compartments of the regulated secretory pathway. In this review, we will focus on the role of zinc in the formation of hormone-containing secretory granules with special emphasis on conditions required for growth hormone dimerization/aggregation. In addition, we highlight the role of zinc transporters that govern the process of zinc homeostasis in the regulated hormone secretion.

Amyloid formation of growth hormone in presence of zinc: Relevance to its storage in secretory granules

“…Previous studies have shown that metal ions facilitate the aggregation of protein/peptide hormones for secretory granule biogenesis 52 . Moreover several previous studies suggested that Zn(II) plays a crucial role in GH secretory granule biogenesis 29 72 80 81 . In this context, when GH aggregation was studied in presence of various metal ions, GH aggregates formed in presence of Zn(II) only showed increased ThT fluorescence ( Figs 2H and 4 F), significant CR binding ( Figs 2 L and 4 G–H) and fibrillar morphology when studied under TEM ( Figs 3 and 4 E).…”

“…Our study also suggests that Zn(II) may participate in secretory granule formation, by assisting in protein aggregation, and also gets co-stored within the secretory granules of GH. Further, in trans-Golgi, Zn(II) could mediate rapid oligomerization of GH, which enables it’s sorting into the regulatory secretory pathway 71 81 . Previous reports have shown that GH binds to Zn(II) with high affinity using its amino acid side chain of H18, H21 and E74, which results in dimerization of GH 29 72 .…”

Transient Neonatal Zinc Deficiency Caused by a Heterozygous G87R Mutation in theZinc Transporter ZnT-2 (SLC30A2)Gene in the Mother Highlighting the Importance of Zn2+for Normal Growth and Development

“…Having discussed the importance of Zn 2+ as well as their individual intracellular transporters it comes without any surprise that an adequate Zn 2+ concentration in the child's plasma is of high importance for normal growth and development [1, 3, 28, 47–49]. …”

Influence of Intracellular Zinc on Cultures of Rat Cardiac Neural Crest Cells

“…Importantly, when cells were incubated in TPEN‐containing media that was supplemented with Zn these effects were not observed, whereas the addition of equimolar amounts of other divalent cations (Cu 2+ , Fe 2+ ) did not abrogate the effects of TPEN, supporting the idea that under the conditions of the current study, the effects of TPEN were primarily due to the ability of this chelator to influence cellular Zn homeostasis. Data obtained with FluoZin‐3 indicate an abundance of Zn ions in cNCC, predominantly located in extranuclear regions with substantial pools in perinuclear organelles, potentially the Golgi and/or the Rough Endoplasmic Reticulum, which have been shown to serve as Zn storage compartments (Petkovic et al., ; Bellomo et al., ). Our images of Zn localization and distribution within cNCC contrast with those obtained using different cellular models, in which free Zn is barely detectable using fluorescent Zn probes (Truong‐Tran, ; Haase, ; Kroncke, ; Besecker, ; Krenn, ) and the concentration of free Zn is estimated to be very low (Bozym et al., ; Colvin et al., ).…”