Fluorescent zinc indicators for neurobiology

Thompson, Richard B.; Peterson, Dwight C.; Mahoney, William M.; Cramer, Michele; Maliwal, Badri P.; Suh, Sang Won; Frederickson, Chris; Fierke, Carol A.; Heřman, Petr

doi:10.1016/s0165-0270(02)00144-9

Cited by 106 publications

(71 citation statements)

References 82 publications

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“…2,3,38). We now have a cadre of fluorophores available with good Zn 2ϩ selectivity and sensitivity (59). Armed with such tools, recent studies of eukaryotic cellular mechanisms of Zn 2ϩ homeostasis have clearly shown similarities with cellular Ca 2ϩ homeostasis, although important differences do exist (for review, see Ref.…”

Section: ϩ Ionophore (Pyrithione) or Metal Chelators [Edta Clioquinmentioning

confidence: 99%

Insights into Zn²⁺ homeostasis in neurons from experimental and modeling studies

Colvin

Bush²,

Volitakis³

et al. 2008

American Journal of Physiology-Cell Physiology

179

122

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To understand the mechanisms of neuronal Zn2+ homeostasis better, experimental data obtained from cultured cortical neurons were used to inform a series of increasingly complex computational models. Total metals (inductively coupled plasma-mass spectrometry), resting metallothionein, 65Zn2+ uptake and release, and intracellular free Zn2+ levels using ZnAF-2F were determined before and after neurons were exposed to increased Zn2+, either with or without the addition of a Zn2+ ionophore (pyrithione) or metal chelators [EDTA, clioquinol (CQ), and N, N, N′, N′-tetrakis(2-pyridylmethyl)ethylenediamine]. Three models were tested for the ability to match intracellular free Zn2+ transients and total Zn2+ content observed under these conditions. Only a model that incorporated a muffler with high affinity for Zn2+, trafficking Zn2+ to intracellular storage sites, was able to reproduce the experimental results, both qualitatively and quantitatively. This “muffler model” estimated the resting intracellular free Zn2+ concentration to be 1.07 nM. If metallothionein were to function as the exclusive cytosolic Zn2+ muffler, the muffler model predicts that the cellular concentration required to match experimental data is greater than the measured resting concentration of metallothionein. Thus Zn2+ buffering in resting cultured neurons requires additional high-affinity cytosolic metal binding moieties. Added CQ, as low as 1 μM, was shown to selectively increase Zn2+ influx. Simulations reproduced these data by modeling CQ as an ionophore. We conclude that maintenance of neuronal Zn2+ homeostasis, when challenged with Zn2+ loads, relies heavily on the function of a high-affinity muffler, the characteristics of which can be effectively studied with computational models.

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Section: ϩ Ionophore (Pyrithione) or Metal Chelators [Edta Clioquinmentioning

confidence: 99%

Insights into Zn²⁺ homeostasis in neurons from experimental and modeling studies

Colvin

Bush²,

Volitakis³

et al. 2008

American Journal of Physiology-Cell Physiology

179

122

View full text Add to dashboard Cite

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“…Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1982, 1987Christensen et al, 1992;Simons, 1993;Thompson et al, 2002), zinc was shown to be present in virtually every tissue of the body where it exists primarily complexed with proteins that serve both metabolic reactions and structural functions. Although there is evidence for the presence of free or loosely bound Zn 2+ ions within the cytoplasm and body fluids (Frederickson, 1989;Reyes, 1996;Simons, 1991;Zalewski et al, 2006), labile ('chelatable') zinc is localized mainly within the synaptic vesicles of glutamatergic nerve terminals throughout the retina and CNS (Beaulieu et al, 1992;Wu et al, 1993; Frederickson and Moncrief, 1994).…”

Section: Introductionmentioning

confidence: 99%

Zinc-mediated feedback at the synaptic terminals of vertebrate photoreceptors

Chappell

Anastassov

Lugo

et al. 2008

Experimental Eye Research

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There is mounting evidence that zinc release from glutamatergic nerve terminals serves as a neuromodulator at synaptic sites within the retina and CNS. However, it has not been possible to reliably measure the concentration of zinc co-released with glutamate in the confines of the synaptic cleft. Thus, much of the evidence supporting this view derives from electrophysiological studies showing the modulatory effects of exogenous zinc on the membrane currents of ligand-and voltagegated channels. In the present study, we took advantage of the unique properties of the glutamatergic photoreceptor terminal to demonstrate a feedback signal mediated by endogenous zinc at the synaptic sites from which it is discharged. Through its ability to block voltage-gated calcium channels in the photoreceptor terminal, zinc suppresses the radial dark current of the visual cell, and reduces its release of glutamate. It follows that chelation of extracellular zinc, e.g., with histidine, will lead to an increase both in the dark current and in the release of glutamate, changes that result in an enhancement of the light-evoked a-wave of the ERG and can account for the b-wave enhancement observed previously after zinc chelation when inner retinal responses were not blocked by aspartate. Keywords skate; retina; rod photoreceptors; zinc; feedback Zinc is unquestionably one of the most ubiquitous trace elements in biological systems, and it is now universally acknowledged that zinc is indispensable to all living organisms: (i) zinc serves as an integral and essential component of scores of enzymes, (ii) it participates in a wide variety of metabolic functions, and (iii) it plays a significant role in translation and transcription of the genetic message. Moreover, zinc is indispensable to the growth and development of all forms of life (cf. reviews by Vallee, 1988;O'Halloran, 1993), and the serious consequences of zinc deficiency have been well documented (cf. Smith et al., 1973;Leopold, 1978;Hambidge, 1981;Krebs et al., 2000;Di Cello et al., 2005;Olmez et al., 2007). With the advent of a range of sensitive detection methods (cf. Danscher et al., 1985;Frederickson et Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1982, 1987Christensen et al., 1992;Simons, 1993;Thompson et al., 2002), zinc was shown to be present in virtually every tissue of the body where it exists primarily complexed with proteins that serve both metabolic reactions and structural functions. Although there is evidence for the presence of free or loosely bound Zn 2+ ions within the cytoplasm and body fluids (Frederickson, ...

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“…Within eukaryotic cells, labile Zn(II) pools have been identified using Zn(II)-responsive fluorophores (7,8). Punctate fluorescent components seen in a myriad of cell types have been termed zincosomes (9), although the compartment has not been fully defined (4).…”

mentioning

confidence: 99%

Mzm1 Influences a Labile Pool of Mitochondrial Zinc Important for Respiratory Function

Atkinson

Khalimonchuk

Smith

et al. 2010

Journal of Biological Chemistry

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Zinc is essential for function of mitochondria as a cofactor for several matrix zinc metalloproteins. We demonstrate that a labile cationic zinc component of low molecular mass exists in the yeast mitochondrial matrix. This zinc pool is homeostatically regulated in response to the cellular zinc status. This pool of zinc is functionally important because matrix targeting of a cytosolic zinc-binding protein reduces the level of labile zinc and interferes with mitochondrial respiratory function. We identified a series of proteins that modulate the matrix zinc pool, one of which is a novel conserved mitochondrial protein designated Mzm1. Mutant mzm1⌬ cells have reduced total and labile mitochondrial zinc, and these cells are hypersensitive to perturbations of the labile pool. In addition, mzm1⌬ cells have a destabilized cytochrome c reductase (Complex III) without any effects on Complexes IV or V. Thus, we have established that a link exists between Complex III integrity and the labile mitochondrial zinc pool.All known mitochondrial zinc-requiring metalloproteins are synthesized in the cytoplasm and must be imported as newly synthesized polypeptides into the organelle as with most resident proteins. Protein import into the mitochondria requires unfolded polypeptides, so folding and metallation occur upon import. Thus, a bioavailable pool of Zn(II) must be maintained within the mitochondria for efficient metallation reactions. The folding of metalloproteins is dependent on the availability and the selective insertion of the appropriate metal ion. Mis-metallation by a non-native metal ion may be deleterious yielding either an inactive protein or a misfolded state prone to aggregation.The zinc mitochondrial metalloproteome is large relative to other metals and distributed throughout the organelle (1). The zinc proteome is heavily populated by proteases and in yeast include the iAAA, mAAA, Oma1, Oct1, Icp55, Atp23, and the MPP protease complex. These proteases all share an essential HEXXH or HXXEH metal-binding motif and whereas many metalloproteinases can be activated in vitro by diverse divalent cations, Zn(II) is likely to be the physiological metal ion bound.Zn(II) is an abundant cofactor for a variety of additional metalloenzymes in mitochondria, including Adh3, Adh4, and

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Fluorescent zinc indicators for neurobiology

Cited by 106 publications

References 82 publications

Insights into Zn²⁺ homeostasis in neurons from experimental and modeling studies

Insights into Zn²⁺ homeostasis in neurons from experimental and modeling studies

Zinc-mediated feedback at the synaptic terminals of vertebrate photoreceptors

Mzm1 Influences a Labile Pool of Mitochondrial Zinc Important for Respiratory Function

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Fluorescent zinc indicators for neurobiology

Cited by 106 publications

References 82 publications

Insights into Zn2+ homeostasis in neurons from experimental and modeling studies

Insights into Zn2+ homeostasis in neurons from experimental and modeling studies

Zinc-mediated feedback at the synaptic terminals of vertebrate photoreceptors

Mzm1 Influences a Labile Pool of Mitochondrial Zinc Important for Respiratory Function

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Insights into Zn²⁺ homeostasis in neurons from experimental and modeling studies

Insights into Zn²⁺ homeostasis in neurons from experimental and modeling studies