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Cited by 620Molecular Sensors and Ion DetectionAdvanced Fluorescence Microscopy TechniquesTrace Elements in Health

Small-Molecule Fluorescent Sensors for Investigating Zinc Metalloneurochemistry

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Nolan, Elizabeth M., Lippard, Stephen J.·2009·Accounts of Chemical Research
DOI 10.1021/ar8001409PMC PMC2646817
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Abstract

The metalloneurochemistry of Zn(II) is of substantial current interest. Zinc is the second most abundant d-block metal ion in the human brain, and its distribution varies with relatively high concentrations found in the hippocampus. Brain zinc is generally divided into two types, protein-bound and loosely bound, the latter also being termed histochemically observable, chelatable, labile, or mobile zinc. The neurophysiological and neuropathological significance of mobile Zn(II) remains enigmatic. Studies of Zn(II) distribution, translocation, and function in vivo require tools for its detection. Because Zn(II) has a closed-shell d(10) configuration and no convenient spectroscopic signature, fluorescence is a well-suited method for monitoring Zn(II) in biological contexts. This Account summarizes work by our laboratory addressing the design, preparation, characterization, and use of small-molecule fluorescent sensors for imaging Zn(II) in living cells and samples of brain tissue. These sensors provide "turn-on" or ratiometric Zn(II) detection in aqueous solution at neutral pH. By making alterations to the Zn(II)-binding unit and fluorophore platform, we have devised sensors with varied photophysical and metal-binding properties. Several of these probes have been applied to image Zn(II) distribution, uptake, and mobilization in a variety of cell types, including neuronal cultures.

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  • The presence of Zn2+ causes a significant enhancement of the emission intensity in 2 and 4, similar to reported Zn fluorescent sensors containing N-(2-pyridylmethyl) arms.

    “However, the presence of Zn2+ causes a significant enhancement of the emission intensity in 2 and 4, (Figures S17 and S18), similar to the reported Zn fluorescent sensors containing N-(2-pyridylmethyl) arms.73,74”

    From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [73]

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Research works printed but not linked: 36

  1. [1]Burdette SC Lippard SJ Meeting of the Minds: Metalloneurochemistry Prod. Nat. Acad. Sci. USA 2003 100 3605 3610 PMC152969 12655069
  2. [3]Que EL Domaille DW Chang CJ Metals in Neurobiology: Probing their Chemistry and Biology with Molecular Imaging Chem. Rev 2008 108 1517 1549 18426241
  3. [4]Frederickson CJ Neurobiology of Zinc and Zinc-Containing Neurons Int. Rev. Neurobiol 1989 31 145 238 2689380
  4. [5]Salazar G Craige B Love R Kalman D Faundez V Vglut1 and ZnT3 Co-targeting Mechanisms Regulate Vesicular Zinc Stores in PC12 Cells J. Cell. Sci 2005 118 1911 1921 15860731
  5. [6]Choi DW Koh JY Zinc and Brain Injury Annu. Rev. Neurosci 1998 21 347 375 9530500
  6. [7]Takeda A Zinc Homeostasis and Functions of Zinc in the Brain Biometals 2001 14 343 351 11831464
  7. [8]Frederickon CJ Koh J-Y Bush AI The Neurobiology of Zinc in Health and Disease Nature Rev. Neurosci 2005 6 449 462 15891778
  8. [9]Assaf SY Chung S-H Release of Endogenous Zn2+ from Brain Tissue During Activity Nature 1984 308 734 736 6717566
  9. [10]Howell GA Welch MG Frederickson CJ Stimulation-Induced Uptake and Release of Zinc in Hippocampal Slices Nature 1984 308 736 738 6717567
  10. [11]Kay AR Evidence for Chelatable Zinc in the Extracellular Space of the Hippocampus, But Little Evidence for Synaptic Release of Zn J. Neurosci 2003 23 6847 6855 12890779 PMC6740710
  11. [12]Qian J Noebels JL Visualization of Transmitter Release with Zinc Fluorescence Detection at the Mouse Hippocampal Mossy Fibre Synapse J. Physiol 2005 566 747 758 15919713 PMC1464795
  12. [13]Takahashi A Camacho P Lechleiter JD Herman B Measurements of Intracellular Calcium Physiol. Rev 1999 79 1089 1125 10508230
  13. [15]Kikuchi K Komatsu K Nagano T Zinc Sensing for Cellular Application Curr. Opin. Chem. Biol 2004 8 182 191 15062780
  14. [17]Lim NC Freake HC Brückner C Illuminating Zinc in Biological Systems Chem. Eur. J 2005 11 38 49 15484196
  15. [20]de Silva AP Gunaratne HQN Gunnlaugsson T Huxley AJM McCoy CP Rademacher JT Rice TE Signaling Recognition Events with Fluorescent Sensors and Switches Chem. Rev 1997 97 1515 1566 11851458
  16. [22]Burdette SC Walkup GK Spingler B Tsien RY Lippard SJ Fluorescent Sensors for Zn2+ Based on a Fluorescein Platform: Synthesis, Properties and Intracellular Distribution J. Am. Chem. Soc 2001 123 7831 7841 11493056
  17. [23]Chang CJ Nolan EM Jaworski J Burdette SC Sheng M Lippard SJ Bright Fluorescent Chemosensor Platforms for Imaging Endogenous Pools of Neuronal Zinc Chem. Biol 2004 11 203 210 15123282
  18. [24]Woodroofe CC Masalha R Barnes KR Frederickson CJ Lippard SJ Membrane-Permeable and -Impermeable Sensors of the Zinpyr Family and Their Application to Imaging of Hippocampal Zinc In Vivo Chem. Biol 2004 11 1659 1666 15610850
  19. [25]Burdette SC Frederickson CJ Bu W Lippard SJ ZP4, an Improved Neuronal Zn2+ Sesnor of the Zinpyr Family J. Am. Chem. Soc 2003 125 1778 1787 12580603
  20. [26]Nolan EM Burdette SC Harvey JH Hilderbrand SA Lippard SJ Synthesis and Characterization of Zinc Sensors Based on a Monosubstituted Fluorescein Platform Inorg. Chem 2004 43 2624 2635 15074981
  21. [27]Chang CJ Nolan EM Jaworski J Okamoto K-I Hayashi Y Sheng M Lippard SJ ZP8, a Neuronal Zinc Sensor with Improved Dynamic Range; Imaging Zinc in Hippocampal Slices with Two-Photon Microscopy Inorg. Chem 2004 43 6774 6779 15476377
  22. [28]Goldsmith CR Lippard SJ 6-Methylpyridyl for Pyridyl Substitution Tunes the Properties of Fluorescent Zinc Sensors of the Zinpyr Family Inorg. Chem 2006 45 555 561 16411690
  23. [29]Nolan EM Jaworski J Racine ME Sheng M Lippard SJ Midrange Affinity Fluorescent Zn(II) Sensors of the Zinpyr Family: Syntheses, Characterization, and Biological Imaging Applications Inorg. Chem 2006 45 9748 9757 17112271 PMC1821072
  24. [32]Hirano T Kikuchi K Urano Y Nagano T Improvement and Biological Applications of Fluorescent Probes for Zinc, ZnAFs J. Am. Chem. Soc 2002 124 6555 6562 12047174
  25. [33]Nolan EM Jaworski J Okamoto K-I Hayashi Y Sheng M Lippard SJ QZ1 and QZ2: Rapid, Reversile Quinoline-Derivatized Fluoresceins for Sensing Biological Zn(II) J. Am. Chem. Soc 2005 127 16812 16823 16316228 PMC1851667
  26. [34]Zecca L Youdim MBH Riederer P Connor JR Crichton RR Iron, Brain Ageing and Neurodegenerative Disorders Nat. Rev. Neurosci 2004 5 863 873 15496864
  27. [35]Goldsmith CR Lippard SJ Analogues of Zinpyr-1 Provide Insight into the Mechanism of Zinc Sensing Inorg. Chem 2006 45 6474 6478 16878961
  28. [36]Nolan EM Lippard SJ The Zinspy Family of Fluorescent Zinc Sensors: Syntheses and Spectroscopic Investigations Inorg. Chem 2004 43 8310 8317 15606177
  29. [37]Nolan EM Ryu JW Jaworski J Feazell RP Sheng M Lippard SJ Zinspy Sensors with Enhanced Dynamic Range for Imaging Neuronal Zinc Uptake and Mobilization J. Am. Chem. Soc 2006 128 15517 15528 17132019 PMC2002492
  30. [38]Sparano BA Shahi SP Koide K Effect of Binding and Conformation on Fluorescence Quenching in New 2′,7′-Dichlorofluorescein Derivatives Org. Lett 2004 6 1947 1949 15176790
  31. [39]Frederickson CJ Kasarskis EJ Ringo D Frederickson RE A Quinoline Fluorescence Method for Visualizing and Assaying the Histochemically Reactive Zinc (Bouton Zinc) in the Brain J. Neurosci. Methods 1987 20 91 103 3600033
  32. [41]Zhang X Lovejoy KS Jasanoff A Lippard SJ Water-Soluble Porphyrins as a Dual-Function Molecular Imaging Platform for MRI and Fluorescence Zinc Sensing Proc. Natl. Acad. Sci. USA 2007 104 10780 10785 17578918 PMC1904115
  33. [42]Burdette SC Lippard SJ The Rhodafluor Family. An Initial Study of Potential Ratiometric Fluorescent Sensors for Zn2+ Inorg. Chem 2002 41 6816 6823 12470079
  34. [43]Woodroofe CC Lippard SJ A Novel Two-Fluorophore Approach to Ratiometric Sensing of Zn2+ J. Am. Chem. Soc 2003 125 11458 11459 13129323
  35. [44]Chang CJ Jaworski J Nolan EM Sheng M Lippard SJ A Tautomeric Zinc Sensor for Ratiometric Fluorescence Imaging: Application to Nitric Oxide-Induced Release of Intracellular Zinc Prod. Natl. Acad. Sci. USA 2004 101 1129 1134 PMC337018 14734801
  36. [45]Woodroofe CC Won AC Lippard SJ Esterase-Activated Two-Fluorophore System for Ratiometric Sensing of Biological Zinc Inorg. Chem 2005 44 3112 3120 15847416

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Authors
Nolan, E. M., & Lippard, S. J.
Affiliations
Massachusetts Institute of Technology (US)
Corresponding author
Lippard, Stephen J.
ORCID
Venue
Accounts of Chemical Research
Publisher
American Chemical Society (ACS)
Published
2008-11-07
Volume
42
Issue
1
Pages
193-203
ISSN
  • 0001-4842 (ISSN-L)
  • 1520-4898
DOI
10.1021/ar8001409
PMC
PMC2646817
OpenAlex
W2087498165
Cited by
620
References
0
Citations by year
2026: 10 · 2025: 12 · 2024: 11 · 2023: 18 · 2022: 12 · 2021: 24 · 2020: 27 · 2019: 31 · 2018: 20 · 2017: 37 · 2016: 39 · 2015: 41 · 2014: 54 · 2013: 74 · 2012: 62
FWCI
21.09
Type
journal article
Language
en
Open access
Locations
  • Accounts of Chemical Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5r01gm065519-16)
  • National Institute of General Medical Sciences (R01‐GM065519)
Topics
  • Physical Sciences › Chemistry › Spectroscopy › Molecular Sensors and Ion Detection
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Advanced Fluorescence Microscopy Techniques
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
Keywords
zinc ion detection, fluorescent sensors, labile zinc, fluorogenic probes, ratiometric detection, hippocampus, zinc mobilization, chemical probes, fluorophores
MeSH terms
Animals, Cells, Cultured, Fluorescent Dyes, Humans, Neurons, Porphyrins, Zinc, Biosensing Techniques, Molecular Structure, Fluorescein

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