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The calcium-activated chloride channel anoctamin 1 acts as a heat sensor in nociceptive neurons

Nature Neuroscience volume 15, pages 1015–1021 (2012)Cite this article

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Abstract

Nociceptors are a subset of small primary afferent neurons that respond to noxious chemical, thermal and mechanical stimuli. Ion channels in nociceptors respond differently to noxious stimuli and generate electrical signals in different ways. Anoctamin 1 (ANO1 also known as TMEM16A) is a Ca2+-activated chloride channel that is essential for numerous physiological functions. We found that ANO1 was activated by temperatures over 44 °C with steep heat sensitivity. ANO1 was expressed in small sensory neurons and was highly colocalized with nociceptor markers, which suggests that it may be involved in nociception. Application of heat ramps to dorsal root ganglion (DRG) neurons elicited robust ANO1-dependent depolarization. Furthermore, knockdown or deletion of ANO1 in DRG neurons substantially reduced nociceptive behavior in thermal pain models. These results indicate that ANO1 is a heat sensor that detects nociceptive thermal stimuli in sensory neurons and possibly mediates nociception.

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Figure 1: Heat activates ANO1.
Figure 2: Synergistic effects of heat and Ca2+ on ANO1 activation.
Figure 3: ANO1 is expressed mainly in nociceptors of DRG neurons.
Figure 4: Heat-induced Cl- currents depolarize DRG neurons.
Figure 5: Pharmacological block or knockdown of ANO1 reduces nocifensive behaviors.
Figure 6: Conditional knockout of ANO1 in DRGs reduces thermal hyperalgesia.

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Acknowledgements

This work was supported by the World Class University project (R31-2011-00101030), the Creative Research Initiatives Program (20120001246) and a grant (2011K000275) from the Brain Research Center of the 21st Century Frontier Research Program funded by of the Ministry of Education and Science and Technology and the National Research Foundation of the Republic of Korea.

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Author notes

  1. Hawon Cho and Young Duk Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Sensory Research Center, Creative Research Initiatives, College of Pharmacy, Seoul National University, Seoul, Republic of Korea

    Hawon Cho, Jesun Lee, Byeongjoon Lee, Tahnbee Kim, Yongwoo Jang & Uhtaek Oh

  2. Department of Pharmacy, College of Pharmacy, CHA University, Gyeonggi-do, Republic of Korea

    Young Duk Yang

  3. Department of Physiology, College of Medicine, Korea University, Seoul, Republic of Korea

    Seung Keun Back & Heung Sik Na

  4. Department of Molecular Genetics and Microbiology and the Genetics Institute, University of Florida, College of Medicine, Gainesville, Florida, USA

    Brian D Harfe

  5. Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA

    Fan Wang

  6. Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, UK

    Ramin Raouf & John N Wood

  7. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea

    Uhtaek Oh

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Contributions

H.C. carried out the patch clamp and behavioral studies and analyzed data. Y.D.Y. and Y.J. performed molecular biological work. J.L. and T.K. performed patch-clamp recordings. B.L., F.W., R.R. and J.N.W. generated CKO mice. S.K.B. and H.S.N. carried out behavioral studies. B.D.H. generated ANO1 systemic knockout mice. U.O. wrote the manuscript and supervised the project.

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Correspondence to Uhtaek Oh.

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The authors declare no competing financial interests.

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Cho, H., Yang, Y., Lee, J. et al. The calcium-activated chloride channel anoctamin 1 acts as a heat sensor in nociceptive neurons. Nat Neurosci 15, 1015–1021 (2012). https://doi.org/10.1038/nn.3111

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