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Vti1b promotes TRPV1 sensitization during inflammatory pain

Sondermann, Julia R.a; Barry, Allison M.a; Jahn, Olafb; Michel, Niklasa; Abdelaziz, Rehama; Kügler, Sebastianc; Gomez-Varela, Davida; Schmidt, Manuelaa,*

doi: 10.1097/j.pain.0000000000001418
Research Paper
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Sensitization of the transient receptor potential ion channel vanilloid 1 (TRPV1) is critically involved in inflammatory pain. To date, manifold signaling cascades have been shown to converge onto TRPV1 and enhance its sensitization. However, many of them also play a role for nociceptive pain, which limits their utility as targets for therapeutic intervention. Here, we show that the vesicle transport through interaction with t-SNAREs homolog 1B (Vti1b) protein promotes TRPV1 sensitization upon inflammation in cell culture but leaves normal functioning of TRPV1 intact. Importantly, the effect of Vti1b can be recapitulated in vivo: Virus-mediated knockdown of Vti1b in sensory neurons attenuated thermal hypersensitivity during inflammatory pain without affecting mechanical hypersensitivity or capsaicin-induced nociceptive pain. Interestingly, TRPV1 and Vti1b are localized in close vicinity as indicated by proximity ligation assays and are likely to bind to each other, either directly or indirectly, as suggested by coimmunoprecipitations. Moreover, using a mass spectrometry–based quantitative interactomics approach, we show that Vti1b is less abundant in TRPV1 protein complexes during inflammatory conditions compared with controls. Alongside, we identify numerous novel and pain state-dependent binding partners of native TRPV1 in dorsal root ganglia. These data represent a unique resource on the dynamics of the TRPV1 interactome and facilitate mechanistic insights into TRPV1 regulation. We propose that inflammation-related differences in the TRPV1 interactome identified here could be exploited to specifically target inflammatory pain in the future.

Discovery of Vti1b as a novel modulator of TRPV1 during inflammatory pain. Application of functional proteomics to define novel and pain state-dependent binding partners of native TRPV1 in dorsal root ganglia.

aSomatosensory Signaling and Systems Biology Group, Max-Planck Institute of Experimental Medicine, Goettingen, Germany. Ms. Barry is now with Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom. Ms. Abdelaziz is now with Oncophysiology Group, Max-Planck Institute of Experimental Medicine, Goettingen, Germany

bProteomics Group, Max-Planck Institute of Experimental Medicine, Goettingen, Germany

cDepartment of Neurology, University Medical Center Goettingen, Goettingen, Germany

Corresponding author. Address: Somatosensory Signaling and Systems Biology Group, Max-Planck Institute of Experimental Medicine, 37075, Goettingen, Germany. Tel.: +49-551-3899-572; fax: +49-551-3899-573. E-mail address: mschmidt@em.mpg.de (M. Schmidt).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Received August 09, 2018

Received in revised form September 08, 2018

Accepted October 09, 2018

© 2019 International Association for the Study of Pain
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