Tmem100 Is a Regulator of TRPA1-TRPV1 Complex and Contributes to Persistent Pain

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Hao-Jui Weng,1,2 Kush N. Patel,1 Nathaniel A. Jeske,3 Sonya M. Bierbower,3 Wangyuan Zou,4 Vinod Tiwari,5 Qin Zheng,1 Zongxiang Tang,6 Gary C.H. Mo,7 Yan Wang,1,8 Yixun Geng,1 Jin Zhang,1,7 Yun Guan,5 Armen N. Akopian,9,*
and Xinzhong Dong1,10,*
1Departments of Neuroscience and Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA 2Department of Dermatology, National Taiwan University Hospital, Taipei City 100, Taiwan
3Department of Physiology, University of Texas Health Science Center, San Antonio, TX 78229, USA
4Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
5Department of Anesthesiology and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA 6Nanjing University of Chinese Medicine, Nanjing 210046, China
7Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA 8West China School of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
9Department of Endodontics, University of Texas Health Science Center, San Antonio, TX 78229, USA
10Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
*Correspondence: akopian@uthscsa.edu (A.N.A.), xdong2@jhmi.edu (X.D.)
http://dx.doi.org/10.1016/j.neuron.2014.12.065

TRPA1 and TRPV1 are crucial pain mediators, but how their interaction contributes to persistent pain is unknown. Here, we identify Tmem100 as a potenti- ating 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 potenti- ates TRPA1 activity in a TRPV1-dependent manner. Mechanistically, Tmem100 weakens the association of TRPA1 and TRPV1, thereby releasing the inhibi- tion of TRPA1 by TRPV1. A Tmem100 mutant, Tmem100-3Q, exerts the opposite effect; i.e., it en- hances the association of TRPA1 and TRPV1 and strongly inhibits TRPA1. Strikingly, a cell-permeable peptide (CPP) containing the C-terminal sequence of Tmem100-3Q mimics its effect and inhibits persistent pain. Our study unveils a context-depen- dent modulation of the TRPA1-V1 complex, and Tmem100-3Q CPP is a promising pain therapy.