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TMEM16C facilitates Na+-activated K+ currents in rat sensory neurons and regulates pain processing

Nature Neuroscience volume 16, pages 1284–1290 (2013)Cite this article

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Abstract

TMEM16C belongs to the TMEM16 family, which includes the Ca2+-activated Cl− channels TMEM16A and TMEM16B and a small-conductance, Ca2+-activated, nonselective cation channel (SCAN), TMEM16F. We found that in rat dorsal root ganglia (DRG) TMEM16C was expressed mainly in the IB4-positive, non-peptidergic nociceptors that also express the sodium-activated potassium (KNa) channel Slack. Together these channel proteins promote KNa channel activity and dampen neuronal excitability. DRG from TMEM16C knockout rats had diminished Slack expression, broadened action potentials and increased excitability. Moreover, the TMEM16C knockout rats, as well as rats with Slack knockdown by intrathecal injection of short interfering RNA, exhibited increased thermal and mechanical sensitivity. Experiments involving heterologous expression in HEK293 cells further showed that TMEM16C modulated the single-channel activity of Slack channels and increased its sodium sensitivity. Our study thus reveals that TMEM16C enhances KNa channel activity in DRG neurons and regulates the processing of pain messages.

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Figure 1: Expression of TMEM16C in dorsal root ganglia and spinal cord.
Figure 2: TMEM16C modulates thermal and mechanical withdrawal thresholds and the action potential width of DRG neurons.
Figure 3: The KNa current is reduced in DRG neurons from TMEM16C knockout rats.
Figure 4: Expression of Slack in the DRG and spinal cord.
Figure 5: TMEM16C interacts with Slack and knockdown of Slack in rat DRGs increases pain responsiveness.
Figure 6: TMEM16C modulates Slack channel activity in HEK293 cells.

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Acknowledgements

We thank M. Tynan La Fontaine and D. Wang for the assistance with the rodent genotyping and husbandry. We thank T. Jin, H. Yang, W. Zhang, W. Ge, T. Wang, C. Peters, S. Xiao, T. Cheng, J. Berg and Z. Guan for technical help and discussions. We thank J. Crawford at Transposagen for administrative assistance. This study is supported by grants from the US National Institutes of Health (NIH) to L.Y.J. and A.I.B. and grants from the NIH and the Commonwealth of Kentucky to E.M.O. Y.-N.J. and L.Y.J. are supported by the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Physiology, University of California, San Francisco, San Francisco, California, USA

    Fen Huang, Yuh-Nung Jan & Lily Yeh Jan

  2. Howard Hughes Medical Institute, San Francisco, California, USA

    Fen Huang, Yuh-Nung Jan & Lily Yeh Jan

  3. Department of Anatomy, University of California, San Francisco, San Francisco, California, USA

    Xidao Wang & Allan I Basbaum

  4. Transposagen Biopharmaceuticals Inc., Lexington, Kentucky, USA

    Eric M Ostertag

  5. Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA

    Tulip Nuwal & Bo Huang

  6. Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, USA

    Yuh-Nung Jan & Lily Yeh Jan

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Contributions

F.H. carried out the immunocytochemistry, molecular biology and electrophysiological studies and analyzed the data; F.H. and X.W. carried out behavioral studies and analyzed the data. T.N. and B.H. performed the STORM imaging and data analysis. E.M.O. generated the knockout rats. F.H., L.Y.J. and A.I.B. wrote the manuscript. L.Y.J. and Y.-N.J. supervised the studies.

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Correspondence to Lily Yeh Jan.

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E.M.O. is employed by Transposagen Biopharmaceuticals, Inc.

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Huang, F., Wang, X., Ostertag, E. et al. TMEM16C facilitates Na+-activated K+ currents in rat sensory neurons and regulates pain processing. Nat Neurosci 16, 1284–1290 (2013). https://doi.org/10.1038/nn.3468

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