Role of TMEM100 in mechanically insensitive nociceptor un-silencing

Abstract

Mechanically silent nociceptors are sensory afferents that are insensitive to noxious mechanical stimuli under normal conditions but become sensitized to such stimuli during inflammation. Using RNA-sequencing and quantitative RT-PCR we demonstrate that inflammation upregulates the expression of the transmembrane protein TMEM100 in silent nociceptors and electrophysiology revealed that over-expression of TMEM100 is required and sufficient to un-silence silent nociceptors in mice. Moreover, we show that mice lacking TMEM100 do not develop secondary mechanical hypersensitivity—i.e., pain hypersensitivity that spreads beyond the site of inflammation—during knee joint inflammation and that AAV-mediated overexpression of TMEM100 in articular afferents in the absence of inflammation is sufficient to induce mechanical hypersensitivity in remote skin regions without causing knee joint pain. Thus, our work identifies TMEM100 as a key regulator of silent nociceptor un-silencing and reveals a physiological role for this hitherto enigmatic afferent subclass in triggering spatially remote secondary mechanical hypersensitivity during inflammation.

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Item Type:	Article
Authors/Creators:	Nees, T.A. Wang, N. Adamek, P. https://orcid.org/0000-0002-7131-6016 Zeitzschel, N. https://orcid.org/0000-0003-4332-7049 Verkest, C. La Porta, C. Schaefer, I. Virnich, J. https://orcid.org/0000-0001-7917-9012 Balkaya, S. Prato, V. Morelli, C. Begay, V. Lee, Y.J. https://orcid.org/0000-0002-3841-1994 Tappe-Theodor, A. https://orcid.org/0000-0002-9343-7580 Lewin, G.R. https://orcid.org/0000-0002-2890-6352 Heppenstall, P.A. Taberner, F.J. Lechner, S.G. https://orcid.org/0000-0001-9402-9127
Copyright, Publisher and Additional Information:	© The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Published: 1 December 2023 Published (online): 5 April 2023 Accepted: 23 March 2023
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds)
Depositing User:	Symplectic Publications
Date Deposited:	03 Aug 2023 10:33
Last Modified:	03 Aug 2023 10:33
Published Version:	https://www.nature.com/articles/s41467-023-37602-w...
Status:	Published
Publisher:	Springer
Identification Number:	10.1038/s41467-023-37602-w
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:201352

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Role of TMEM100 in mechanically insensitive nociceptor un-silencing

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