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STIM1 thermosensitivity defines the optimal preference temperature for warm sensation in mice

Cell Research (2019) | Download Citation

Abstract

Mammals possess a remarkable ability to sense subtle temperature deviations from the thermoneutral skin temperature of ~33 °C, which ensures precise warm sensation. However, the underlying mechanisms remain unclear. Here we show that STIM1, an endoplasmic reticulum (ER) resident transmembrane protein that responds to both ER Ca2+ depletion and heat, mediates temperature-induced Ca2+ influx in skin keratinocytes via coupling to Orai Ca2+ channels in plasma membrane. Behaviorally, the keratinocyte-specific knockout of STIM1 shifts the optimal preference temperature (OPT) of mice from ~32 °C to ~34 °C, resulting in a strikingly reversed preference between 32 °C and 34 °C. Importantly, the thermally inactive STIM1-ΔK knock-in mice show altered OPT and warm preference behaviors as well, demonstrating the requirement of STIM1 thermosensitivity for warm sensation. Furthermore, the wild-type and mutant mice prefer temperatures closer to their respective OPTs, but poorly distinguish temperatures that are equally but oppositely deviated from their OPTs. Mechanistically, keratinocyte STIM1 affects the in vivo warm responses of sensory neurons by likely involving TRPA1 as a downstream transduction channel. Collectively, our data suggest that STIM1 serves as a novel in vivo thermosensor in keratinocytes to define the OPT, which might be utilized as a peripheral reference temperature for precise warm sensation.

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Acknowledgements

This study was initiated in Dr. Ardem Patapoutian’s laboratory, and we thank him for his tremendous support. We thank Dr. Anjana Rao for generously sharing the STIM1fl/fl mice; Drs. Donald Gill and Youjun Wang (Beijing Normal University) for sharing the Orai-KO-HEK cell lines; Drs. Sanjue Hu, Junlin Xin and Xiaohui Liu for technical help; R. Eddins, R. Miramontes and M. Frazer for managing the constitutive STIM1 KO mouse line, and J. Avis, C. Wilmot, C. Cienfuegos and E. Hesek for technical help in the generation and genotyping of the mice; the animal core facility at Tsinghua University for maintaining the other lines of mice used in the study. We thank Drs. Ardem Patapoutian (The Scripps Research Institute), Mohamed Trebak (Pennsylvania State University College of Medicine), Hongzhen Hu (Washington University), Yubin Zhou (Texas A&M University Health Science Center) and Youjun Wang for critically reading the manuscript. This work was supported by the National Natural Science Foundation of China (31371118, 31825014, 31630090 and 31422027), the National Key R&D Program of China (2016YFA0500402 and 2015CB910102), and the Young Thousand Talent Program to B.X.

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Author notes

  1. These authors contributed equally: Xiaoling Liu, Haiping Wang, Yan Jiang, Qin Zheng

Affiliations

  1. State Key Laboratory of Membrane Biology; Tsinghua-Peking Joint Center for Life Sciences; IDG/McGovern Institute for Brain Research; School of Pharmaceutical Sciences, Tsinghua University, 100084, Beijing, China

    • Xiaoling Liu
    • , Haiping Wang
    • , Yan Jiang
    • , Mingmin Zhang
    •  & Bailong Xiao
  2. Departments of Neuroscience, Neurosurgery, and Dermatology, Center of Sensory Biology, Howard Hughes Medical Institute, the Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    • Qin Zheng
    •  & Xinzhong Dong
  3. Genomics Institute of the Novartis Research Foundation, San Diego, CA, 92121, USA

    • Matt Petrus
    •  & Christian Schmedt
  4. Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, 100875, Beijing, China

    • Sisi Zheng

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Contributions

X. L. and Y. J. generated the STIM1-ΔK knock-in mice, designed and carried out the cellular and biochemical experiments and analyzed the data. H. W. and M. P. performed behavioral experiments and analyzed the data. Q. Z. performed in vivo DRG Ca2+ imaging studies and analyzed the data. M. Z. helped the cellular experiments. S. Z. generated the Orai-KO-HEK cell lines. C. S. supervised the generation and genotyping of the constitutive STIM1-knockout mice. D. X. supervised the in vivo DRG Ca2+ imaging studies. B. X. conceived and supervised the project, conceptualized the model, made figures and wrote the paper with help from all the authors. All authors read and discussed the paper.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Bailong Xiao.

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https://doi.org/10.1038/s41422-018-0129-0