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Sub-nanomolar sensitive GZnP3 reveals TRPML1-mediated neuronal Zn2+ signals

Author

Listed:
  • Taylor F. Minckley

    (University of Denver)

  • Chen Zhang

    (University of Denver)

  • Dylan H. Fudge

    (University of Denver)

  • Anna M. Dischler

    (University of Denver)

  • Kate D. LeJeune

    (University of Denver)

  • Haoxing Xu

    (University of Michigan, 4114 Biological Sciences Building, 1105 North University)

  • Yan Qin

    (University of Denver)

Abstract

Although numerous fluorescent Zn2+ sensors have been reported, it is unclear whether and how Zn2+ can be released from the intracellular compartments into the cytosol due to a lack of probes that can detect physiological dynamics of cytosolic Zn2+. Here, we create a genetically encoded sensor, GZnP3, which demonstrates unprecedented sensitivity for Zn2+ at sub-nanomolar concentrations. Using GZnP3 as well as GZnP3-derived vesicular targeted probes, we provide the first direct evidence that Zn2+ can be released from endolysosomal vesicles to the cytosol in primary hippocampal neurons through the TRPML1 channel. Such TRPML1-mediated Zn2+ signals are distinct from Ca2+ in that they are selectively present in neurons, sustain longer, and are significantly higher in neurites as compared to the soma. Together, our work not only creates highly sensitive probes for investigating sub-nanomolar Zn2+ dynamics, but also reveals new pools of Zn2+ signals that can play critical roles in neuronal function.

Suggested Citation

  • Taylor F. Minckley & Chen Zhang & Dylan H. Fudge & Anna M. Dischler & Kate D. LeJeune & Haoxing Xu & Yan Qin, 2019. "Sub-nanomolar sensitive GZnP3 reveals TRPML1-mediated neuronal Zn2+ signals," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12761-x
    DOI: 10.1038/s41467-019-12761-x
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    Cited by:

    1. Jemil Ahmed & Tessa C. Fitch & Courtney M. Donnelly & Johnson A. Joseph & Tyler D. Ball & Mikaela M. Bassil & Ahyun Son & Chen Zhang & Aurélie Ledreux & Scott Horowitz & Yan Qin & Daniel Paredes & Sun, 2022. "Foldamers reveal and validate therapeutic targets associated with toxic α-synuclein self-assembly," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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