Highly dynamic and sensitive NEMOer calcium indicators for imaging ER calcium signals in excitable cells

Wenjia Gu; Jia Hui Chen; Yiyin Zhang; Zhirong Wang; Jia Li; Sijia Wang; Hanhan Zhang; Amin Jiang; Ziyi Zhong; Jiaxuan Zhang; Ze Xu; Panpan Liu; Chao Xi; Tingting Hou; Donald L. Gill; Dong Li; Yu Mu; Shi Qiang Wang; Ai Hui Tang; Youjun Wang

doi:10.1038/s41467-025-58705-6

Highly dynamic and sensitive NEMOer calcium indicators for imaging ER calcium signals in excitable cells

Wenjia Gu, Jia Hui Chen, Yiyin Zhang, Zhirong Wang, Jia Li, Sijia Wang, Hanhan Zhang, Amin Jiang, Ziyi Zhong, Jiaxuan Zhang, Ze Xu, Panpan Liu, Chao Xi, Tingting Hou, Donald L. Gill, Dong Li, Yu Mu, Shi Qiang Wang, Ai Hui Tang, Youjun Wang

Department of Cell and Biological Systems

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

The Endoplasmic/sarcoplasmic reticulum (ER/SR) is central to calcium (Ca²⁺) signaling, yet current genetically encoded Ca²⁺ indicators (GECIs) cannot detect elementary Ca²⁺ release events from ER/SR, particularly in muscle cells. Here, we report NEMOer, a set of organellar GECIs, to efficiently capture ER Ca²⁺ dynamics with increased sensitivity and responsiveness. NEMOer indicators exhibit dynamic ranges an order of magnitude larger than G-CEPIA1er, enabling 2.7-fold more sensitive detection of Ca²⁺ transients in both non-excitable and excitable cells. The ratiometric version further allows super-resolution monitoring of local ER Ca²⁺ homeostasis and dynamics. Notably, NEMOer-f enabled the inaugural detection of Ca²⁺ blinks, elementary Ca²⁺ releasing signals from the SR of cardiomyocytes, as well as in vivo spontaneous SR Ca²⁺ releases in zebrafish. In summary, the highly dynamic NEMOer sensors expand the repertoire of organellar Ca²⁺ sensors that allow real-time monitoring of intricate Ca²⁺ dynamics and homeostasis in live cells with high spatiotemporal resolution.

Original language	English (US)
Article number	3472
Journal	Nature communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-58705-6
State	Published - Dec 2025

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Gu, W., Chen, J. H., Zhang, Y., Wang, Z., Li, J., Wang, S., Zhang, H., Jiang, A., Zhong, Z., Zhang, J., Xu, Z., Liu, P., Xi, C., Hou, T., Gill, D. L., Li, D., Mu, Y., Wang, S. Q., Tang, A. H., & Wang, Y. (2025). Highly dynamic and sensitive NEMOer calcium indicators for imaging ER calcium signals in excitable cells. Nature communications, 16(1), Article 3472. https://doi.org/10.1038/s41467-025-58705-6

@article{fe2106315c194e08b0944ccfc21e94b3,

title = "Highly dynamic and sensitive NEMOer calcium indicators for imaging ER calcium signals in excitable cells",

abstract = "The Endoplasmic/sarcoplasmic reticulum (ER/SR) is central to calcium (Ca2+) signaling, yet current genetically encoded Ca2+ indicators (GECIs) cannot detect elementary Ca2+ release events from ER/SR, particularly in muscle cells. Here, we report NEMOer, a set of organellar GECIs, to efficiently capture ER Ca2+ dynamics with increased sensitivity and responsiveness. NEMOer indicators exhibit dynamic ranges an order of magnitude larger than G-CEPIA1er, enabling 2.7-fold more sensitive detection of Ca2+ transients in both non-excitable and excitable cells. The ratiometric version further allows super-resolution monitoring of local ER Ca2+ homeostasis and dynamics. Notably, NEMOer-f enabled the inaugural detection of Ca2+ blinks, elementary Ca2+ releasing signals from the SR of cardiomyocytes, as well as in vivo spontaneous SR Ca2+ releases in zebrafish. In summary, the highly dynamic NEMOer sensors expand the repertoire of organellar Ca2+ sensors that allow real-time monitoring of intricate Ca2+ dynamics and homeostasis in live cells with high spatiotemporal resolution.",

author = "Wenjia Gu and Chen, \{Jia Hui\} and Yiyin Zhang and Zhirong Wang and Jia Li and Sijia Wang and Hanhan Zhang and Amin Jiang and Ziyi Zhong and Jiaxuan Zhang and Ze Xu and Panpan Liu and Chao Xi and Tingting Hou and Gill, \{Donald L.\} and Dong Li and Yu Mu and Wang, \{Shi Qiang\} and Tang, \{Ai Hui\} and Youjun Wang",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s41467-025-58705-6",

language = "English (US)",

volume = "16",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Gu, W, Chen, JH, Zhang, Y, Wang, Z, Li, J, Wang, S, Zhang, H, Jiang, A, Zhong, Z, Zhang, J, Xu, Z, Liu, P, Xi, C, Hou, T, Gill, DL, Li, D, Mu, Y, Wang, SQ, Tang, AH & Wang, Y 2025, 'Highly dynamic and sensitive NEMOer calcium indicators for imaging ER calcium signals in excitable cells', Nature communications, vol. 16, no. 1, 3472. https://doi.org/10.1038/s41467-025-58705-6

TY - JOUR

T1 - Highly dynamic and sensitive NEMOer calcium indicators for imaging ER calcium signals in excitable cells

AU - Gu, Wenjia

AU - Chen, Jia Hui

AU - Zhang, Yiyin

AU - Wang, Zhirong

AU - Li, Jia

AU - Wang, Sijia

AU - Zhang, Hanhan

AU - Jiang, Amin

AU - Zhong, Ziyi

AU - Zhang, Jiaxuan

AU - Xu, Ze

AU - Liu, Panpan

AU - Xi, Chao

AU - Hou, Tingting

AU - Gill, Donald L.

AU - Li, Dong

AU - Mu, Yu

AU - Wang, Shi Qiang

AU - Tang, Ai Hui

AU - Wang, Youjun

PY - 2025/12

Y1 - 2025/12

N2 - The Endoplasmic/sarcoplasmic reticulum (ER/SR) is central to calcium (Ca2+) signaling, yet current genetically encoded Ca2+ indicators (GECIs) cannot detect elementary Ca2+ release events from ER/SR, particularly in muscle cells. Here, we report NEMOer, a set of organellar GECIs, to efficiently capture ER Ca2+ dynamics with increased sensitivity and responsiveness. NEMOer indicators exhibit dynamic ranges an order of magnitude larger than G-CEPIA1er, enabling 2.7-fold more sensitive detection of Ca2+ transients in both non-excitable and excitable cells. The ratiometric version further allows super-resolution monitoring of local ER Ca2+ homeostasis and dynamics. Notably, NEMOer-f enabled the inaugural detection of Ca2+ blinks, elementary Ca2+ releasing signals from the SR of cardiomyocytes, as well as in vivo spontaneous SR Ca2+ releases in zebrafish. In summary, the highly dynamic NEMOer sensors expand the repertoire of organellar Ca2+ sensors that allow real-time monitoring of intricate Ca2+ dynamics and homeostasis in live cells with high spatiotemporal resolution.

AB - The Endoplasmic/sarcoplasmic reticulum (ER/SR) is central to calcium (Ca2+) signaling, yet current genetically encoded Ca2+ indicators (GECIs) cannot detect elementary Ca2+ release events from ER/SR, particularly in muscle cells. Here, we report NEMOer, a set of organellar GECIs, to efficiently capture ER Ca2+ dynamics with increased sensitivity and responsiveness. NEMOer indicators exhibit dynamic ranges an order of magnitude larger than G-CEPIA1er, enabling 2.7-fold more sensitive detection of Ca2+ transients in both non-excitable and excitable cells. The ratiometric version further allows super-resolution monitoring of local ER Ca2+ homeostasis and dynamics. Notably, NEMOer-f enabled the inaugural detection of Ca2+ blinks, elementary Ca2+ releasing signals from the SR of cardiomyocytes, as well as in vivo spontaneous SR Ca2+ releases in zebrafish. In summary, the highly dynamic NEMOer sensors expand the repertoire of organellar Ca2+ sensors that allow real-time monitoring of intricate Ca2+ dynamics and homeostasis in live cells with high spatiotemporal resolution.

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U2 - 10.1038/s41467-025-58705-6

DO - 10.1038/s41467-025-58705-6

M3 - Article

C2 - 40216787

AN - SCOPUS:105002970841

SN - 2041-1723

VL - 16

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 3472

ER -

Highly dynamic and sensitive NEMOer calcium indicators for imaging ER calcium signals in excitable cells

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