Fluorescent Protein-Based Sensors for Detecting Essential Metal Ions across the Tree of Life
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Genetically encoded fluorescent metal ion sensors are powerful tools for elucidating metal dynamics in living systems. Over the last 25 years since the first examples of genetically encoded fluorescent protein-based calcium indicators, this toolbox of probes has expanded to include other essential and non-essential metal ions. Collectively, these tools have illuminated fundamental aspects of metal homeostasis and trafficking that are crucial to fields ranging from neurobiology to human nutrition. Despite these advances, much of the application of metal ion sensors remains limited to mammalian cells and tissues and a limited number of essential metals. Applications beyond mammalian systems and in vivo applications in living organisms have primarily used genetically encoded calcium ion sensors. The aim of this Perspective is to provide, with the support of historical and recent literature, an updated and critical view of the design and use of fluorescent protein-based sensors for detecting essential metal ions in various organisms. We highlight the historical progress and achievements with calcium sensors and discuss more recent advances and opportunities for the detection of other essential metal ions. We also discuss outstanding challenges in the field and directions for future studies, including detecting a wider variety of metal ions, developing and implementing a broader spectral range of sensors for multiplexing experiments, and applying sensors to a wider range of single- and multi-species biological systems.
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It is becoming possible to better visualize metals in motion with sensitive analytical tools, including an ever-increasing set of sensors to monitor chelatable metal ions in living cells.
“Together with sensitive analytical tools, including an ever-increasing set of sensors to monitor chelatable metal ions in living cells,223−225 it is becoming possible to better visualize metals in motion.”
From Metals in Motion: Understanding Labile Metal Pools in Bacteria (2025) · cites this paper as [223]
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Lam, A. J., St-Pierre, F., Gong, Y., Marshall, J. D., Cranfill, P. J., Baird, M. A., McKeown, M. R., Wiedenmann, J., Davidson, M. W., Schnitzer, M. J., et al. (2012) · Nature Methods · doi:10.1038/nmeth.2171 · Cited by 732 · see citing works
Regulation of Potassium Homeostasis
Palmer, B. F. (2015) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.08580813 · Cited by 535 · see citing works
Spontaneous network activity visualized by ultrasensitive Ca2+ indicators, yellow Cameleon-Nano
Horikawa, K., Yamada, Y., Matsuda, T., Kobayashi, K., Hashimoto, M., Matsu-ura, T., Miyawaki, A., Michikawa, T., Mikoshiba, K., & Nagai, T. (2010) · Nature Methods · doi:10.1038/nmeth.1488 · Cited by 338 · see citing works
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Metals in Motion: Understanding Labile Metal Pools in Bacteria
Helmann, J. D. (2025) · Biochemistry · doi:10.1021/acs.biochem.4c00726 · Cited by 49 · see citing works
- Authors
- Jensen, G. C., Janis, M. K., Nguyen, H. N., David, O. W., & Zastrow, M. L.
- Affiliations
- University of Houston (US)
- Corresponding author
- Zastrow, Melissa L.
- Venue
- ACS Sensors
- Publisher
- American Chemical Society (ACS)
- Published
- 2024-04-08
- Volume
- 9
- Issue
- 4
- Pages
- 1622-1643
- ISSN
- 2379-3694 (ISSN-L)
- PMC
- PMC11073808
- OpenAlex
- W4394580513
- Cited by
- 25
- References
- 3
- Citations by year
- 2026: 6 · 2025: 17 · 2024: 2
- FWCI
- 1.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- ACS Sensors (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Welch Foundation (E-2176-20230405)
- U.S. Department of Health and Human Services (R35 GM138223)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Advanced Fluorescence Microscopy Techniques
- Physical Sciences › Chemistry › Spectroscopy › Molecular Sensors and Ion Detection
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › bioluminescence and chemiluminescence research
- Keywords
- metal ion sensors, calcium sensor, metal homeostasis, metal trafficking, in vivo imaging, multiplexed sensing
- MeSH terms
- Animals, Calcium, Fluorescent Dyes, Humans, Ions, Luminescent Proteins, Metals, Biosensing Techniques
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