@article{371d29d6211b497f9d6c911369a41eab,
title = "Tmem100 Is a Regulator of TRPA1-TRPV1 Complex and Contributes to Persistent Pain",
abstract = "TRPA1 and TRPV1 are crucial pain mediators, but how their interaction contributes to persistent pain is unknown. Here, we identify Tmem100 as a potentiating modulator of TRPA1-V1 complexes. Tmem100 is coexpressed and forms a complex with TRPA1 and TRPV1 in DRG neurons. Tmem100-deficient mice show a reduction in inflammatory mechanical hyperalgesia and TRPA1- but not TRPV1-mediated pain. Single-channel recording in a heterologous system reveals that Tmem100 selectively potentiatesTRPA1 activity in a TRPV1-dependent manner. Mechanistically, Tmem100 weakens the association of TRPA1 and TRPV1, thereby releasing the inhibitionof TRPA1 by TRPV1. A Tmem100 mutant, Tmem100-3Q, exerts the opposite effect; i.e., it enhances theassociation of TRPA1 and TRPV1 and strongly inhibits TRPA1. Strikingly, a cell-permeable peptide(CPP) containing the C-terminal sequence ofTmem100-3Q mimics its effect and inhibits persistent pain. Our study unveils a context-dependent modulation of the TRPA1-V1 complex, and Tmem100-3Q CPP is a promising pain therapy.",
author = "Weng, {Hao Jui} and Patel, {Kush N.} and Jeske, {Nathaniel A.} and Bierbower, {Sonya M.} and Wangyuan Zou and Vinod Tiwari and Qin Zheng and Zongxiang Tang and Mo, {Gary C.H.} and Yan Wang and Yixun Geng and Jin Zhang and Yun Guan and Akopian, {Armen N.} and Xinzhong Dong",
note = "Funding Information: We thank Dr. Bo Xiao at West China Hospital, Sichuan University, China for making the Tmem100 conditional knockout targeting construct. We thank Chip Hawkins and Holly Wellington of the Mouse ES cell Core (P30NS050274) at Johns Hopkins University School of Medicine for assistance with the generation of Tmem100 conditional knockout mice. We also thank Dr. Manuela Schmidt at the Max-Planck-Institute for Experimental Medicine in Germany for providing the anti-TRPA1 antibody, Dr. Michael Caterina at Johns Hopkins University for providing anti-TRPV1 antibody, Dr. Fan Wang at Duke University for providing Advillin-Cre mice, and Dr. Diana Bautista at University of California, Berkeley for providing F11 cell lines. This work was supported by NIH Grants (R01DE022750 and R01GM087369) to X.D., who is an Early Career Scientist of the Howard Hughes Medical Institute. This work was also supported by NIH grants (R01DE019311) to A.N.A. and (R01NS082746) N.A.J. and a NRSA Fellowship (F32NS079148) to S.M.B. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc. Copyright: Copyright 2015 Elsevier B.V., All rights reserved.",
year = "2015",
month = feb,
day = "18",
doi = "10.1016/j.neuron.2014.12.065",
language = "English",
volume = "85",
pages = "833--846",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "4",
}