Role of TMEM100 in mechanically insensitive nociceptor un-silencing

Timo A. Nees, Na Wang, Pavel Adamek, Nadja Zeitzschel, Clement Verkest, Carmen Porta, Irina Schaefer, Julie Virnich, Selin Balkaya, Vincenzo Prato, Chiara Morelli, Valerie Begay, Young Jae Lee, Anke Tappe-Theodor, Gary R. Lewin, Paul A. Heppenstall, Francisco J. Taberner and Stefan G. Lechner ()
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Timo A. Nees: Heidelberg University
Na Wang: Yan’an University
Pavel Adamek: University Medical Center Hamburg-Eppendorf
Nadja Zeitzschel: University Medical Center Hamburg-Eppendorf
Clement Verkest: University Medical Center Hamburg-Eppendorf
Carmen Porta: Heidelberg University
Irina Schaefer: Heidelberg University
Julie Virnich: University Medical Center Hamburg-Eppendorf
Selin Balkaya: University Medical Center Hamburg-Eppendorf
Vincenzo Prato: Heidelberg University
Chiara Morelli: SISSA: Scuola Internazionale Superiore di Studi Avanzati
Valerie Begay: Max Delbrück Center for Molecular Medicine
Young Jae Lee: Gachon University College of Medicine
Anke Tappe-Theodor: Heidelberg University
Gary R. Lewin: Max Delbrück Center for Molecular Medicine
Paul A. Heppenstall: SISSA: Scuola Internazionale Superiore di Studi Avanzati
Francisco J. Taberner: Heidelberg University
Stefan G. Lechner: Heidelberg University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37602-w

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