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Visualization of Peroxynitrite-Induced Changes of Labile Zn<sup>2+</sup> in the Endoplasmic Reticulum with Benzoresorufin-Based Fluorescent Probes

Abstract

Zn<sup>2+</sup> plays essential roles in biology, and the homeostasis of Zn<sup>2+</sup> is tightly regulated in all cells. Subcellular distribution and trafficking of labile Zn<sup>2+</sup>, and its inter-relation with reactive nitrogen species, are poorly understood due to the scarcity of appropriate imaging tools. We report a new family of red-emitting fluorescent sensors for labile Zn<sup>2+</sup>, ZBR1–3, based on a benzo­resorufin platform functionalized with dipicolyl­amine or picolyl­amine-derived metal binding groups. In combination, the pendant amines and fluorophore afford an [N<sub>3</sub>O] binding motif that resembles that of previously reported fluorescein-based sensors of the Zinpyr family, reproducing well their binding capabilities and yielding comparable <i>K</i><sub>d</sub> values in the sub-nanomolar and picomolar ranges. The ZBR sensors display up to 8.4-fold emission fluorescence enhancement upon Zn<sup>2+</sup> binding in the cuvette, with similar responses obtained in live cells using standard wide-field fluorescence microscopy imaging. The new sensors localize spontaneously in the endoplasmic reticulum (ER) of various tested cell lines, allowing for organelle-specific monitoring of zinc levels in live cells. Study of ER zinc levels in neural stem cells treated with a peroxy­nitrite generator, Sin-1, revealed an immediate decrease in labile Zn<sup>2+</sup> thus providing evidence for a direct connection between ER stress and ER Zn<sup>2+</sup> homeostasis

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The Francis Crick Institute

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Last time updated on 12/02/2018

This paper was published in The Francis Crick Institute.

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