Genetically-encoded FRET-based sensors for monitoring Zn<sup>2+</sup> in living cells

Hessels, AM Anne; Merkx, Maarten

doi:10.1039/c4mt00179f

Cited by 88 publications

(75 citation statements)

References 39 publications

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“…While similar values were returned for all probes when located in the cytosol, i.e. 0·1-1·5 nM (7,8,28,30,33) (Fig. 2), in line with results using (31) , white: eCALWY-4 (7) , yellow: eZinCh-1 (7) .…”

Section: Imaging Free Zn 2+ In Living Cellssupporting

confidence: 67%

“…mitochondria and lysosomes) (27) . Genetically-encoded zinc sensors use Fӧrster Resonance Energy Transfer as the sensing modality and consist of a donor and acceptor fluorescent protein linked by a zinc-binding peptide sequence (28) . Two families have been designed by the Palmer group based on zinc fingers: Zif-and Zap-sensors.…”

Section: Imaging Free Zn 2+ In Living Cellsmentioning

confidence: 99%

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Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?

et al. 2015

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Zinc is an important micronutrient, essential in the diet to avoid a variety of conditions associated with malnutrition such as diarrhoea and alopecia. Lowered circulating levels of zinc are also found in diabetes mellitus, a condition which affects one in twelve of the adult population and whose treatments consume approximately 10 % of healthcare budgets. Zn 2+ ions are essential for a huge range of cellular functions and, in the specialised pancreatic β-cell, for the storage of insulin within the secretory granule. Correspondingly, genetic variants in the SLC30A8 gene, which encodes the diabetes-associated granule-resident Zn 2+ transporter ZnT8, are associated with an altered risk of type 2 diabetes. Here, we focus on (i) recent advances in measuring free zinc concentrations dynamically in subcellular compartments, and (ii) studies dissecting the role of intracellular zinc in the control of glucose homeostasis in vitro and in vivo. We discuss the effects on insulin secretion and action of deleting or overexpressing Slc30a8 highly selectively in the pancreatic β-cell, and the role of zinc in insulin signalling. While modulated by genetic variability, healthy levels of dietary zinc, and hence normal cellular zinc homeostasis, are likely to play an important role in the proper release and action of insulin to maintain glucose homeostasis and lower diabetes risk.

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Section: Imaging Free Zn 2+ In Living Cellssupporting

confidence: 67%

Section: Imaging Free Zn 2+ In Living Cellsmentioning

confidence: 99%

Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?

et al. 2015

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“…The small SEMs in Zn 2+ intensity and cell numbers throughout the study point to a relatively small sampling error. (32)]. ZP-1 gave a strong, reproducible signal when injected intraocularly and had no apparent systemic effects.…”

Section: Methodsmentioning

confidence: 99%

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

Andereggen

Yuki

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

125

129

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Retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate their axons once the optic nerve has been injured and soon begin to die. Whereas RGC death and regenerative failure are widely viewed as being cell-autonomous or influenced by various types of glia, we report here that the dysregulation of mobile zinc (Zn 2+ ) in retinal interneurons is a primary factor. Within an hour after the optic nerve is injured, Zn 2+ increases several-fold in retinal amacrine cell processes and continues to rise over the first day, then transfers slowly to RGCs via vesicular release. Zn 2+ accumulation in amacrine cell processes involves the Zn 2+ transporter protein ZnT-3, and deletion of slc30a3, the gene encoding ZnT-3, promotes RGC survival and axon regeneration. Intravitreal injection of Zn 2+ chelators enables many RGCs to survive for months after nerve injury and regenerate axons, and enhances the prosurvival and regenerative effects of deleting the gene for phosphatase and tensin homolog (pten). Importantly, the therapeutic window for Zn 2+ chelation extends for several days after nerve injury. These results show that retinal Zn 2+ dysregulation is a major factor limiting the survival and regenerative capacity of injured RGCs, and point to Zn 2+ chelation as a strategy to promote long-term RGC protection and enhance axon regeneration.T he optic nerve has been widely used to investigate the response of CNS neurons to injury because of its accessibility, anatomy, and functional importance. Under normal circumstances, retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate axons after the optic nerve has been damaged and soon undergo cell death, leaving victims of traumatic or ischemic nerve injury or degenerative conditions, such as glaucoma, with permanent visual losses. Optic nerve injury leads to numerous pathological changes in RGCs and reversing some of these changes improves cell survival, although these effects are often transitory and for the most part promote little or no axon regeneration (1-10). Regeneration per se can be induced by intraocular inflammation combined with elevated cAMP (11, 12), counteracting cell-intrinsic (13-15) or cellextrinsic (16, 17) suppressors of axon growth, oncomodulin and other growth factors (18-22), or elevated physiological activity (23,24). Some of these treatments act synergistically and enable a modest number of RGCs to reestablish connections with appropriate target areas in the brain (25-27). However, although these studies show that successful regeneration can occur in principle, most RGCs eventually die after optic nerve injury, and to date only a small fraction of surviving RGCs have been induced to regenerate axons (27). These observations imply the existence of other major, as yet unknown suppressors of cell survival and regeneration. Our results point to zinc dysregulation as a critical factor.Zinc is essential for many cellular functions. Covalently bound zinc is required for the activity of numerous enzymes and t...

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“…There is an apparent discrepancy between nanomolar levels of concentration of free zinc in cytosol and endoplasmic reticulum (55)(56)(57)(58) where Hh autoprocessing occurs, and the M K i of zinc inhibition of Hh autoprocessing measured in vitro. A similar unresolved conundrum exists in many zinc transporters whose measured K m values are in the M range (59 -63).…”

Section: Gli Glimentioning

confidence: 99%

Zinc Inhibits Hedgehog Autoprocessing

Xie

Owen

Xia³

et al. 2015

Journal of Biological Chemistry

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Background: In many types of cancers zinc deficiency and overproduction of Hedgehog (Hh) ligand co-exist. Results: Zinc binds to the active site of the Hedgehog-intein (Hint) domain and inhibits Hh ligand production both in vitro and in cell culture. Conclusion: Zinc influences the Hh autoprocessing.Significance: This study uncovers a novel mechanistic link between zinc and the Hh signaling pathway.

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Genetically-encoded FRET-based sensors for monitoring Zn²⁺ in living cells

Abstract: We discuss the development and application of genetically-encoded FRET sensors as attractive tools to study intracellular Zn2+ homeostasis and signaling.

Cited by 88 publications

References 39 publications

Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?

Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

Zinc Inhibits Hedgehog Autoprocessing

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Genetically-encoded FRET-based sensors for monitoring Zn2+ in living cells

Abstract: We discuss the development and application of genetically-encoded FRET sensors as attractive tools to study intracellular Zn2+ homeostasis and signaling.

Cited by 88 publications

References 39 publications

Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?

Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

Zinc Inhibits Hedgehog Autoprocessing

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Product

Resources

About

Genetically-encoded FRET-based sensors for monitoring Zn²⁺ in living cells