1. Academic Validation
  2. Tmem100 Is a Regulator of TRPA1-TRPV1 Complex and Contributes to Persistent Pain

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

  • Neuron. 2015 Feb 18;85(4):833-46. doi: 10.1016/j.neuron.2014.12.065.
Hao-Jui Weng 1 Kush N Patel 2 Nathaniel A Jeske 3 Sonya M Bierbower 3 Wangyuan Zou 4 Vinod Tiwari 5 Qin Zheng 2 Zongxiang Tang 6 Gary C H Mo 7 Yan Wang 8 Yixun Geng 2 Jin Zhang 9 Yun Guan 5 Armen N Akopian 10 Xinzhong Dong 11
Affiliations

Affiliations

  • 1 Departments of Neuroscience and Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Dermatology, National Taiwan University Hospital, Taipei City 100, Taiwan.
  • 2 Departments of Neuroscience and Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
  • 3 Department of Physiology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
  • 4 Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
  • 5 Department of Anesthesiology and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
  • 6 Nanjing University of Chinese Medicine, Nanjing 210046, China.
  • 7 Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
  • 8 Departments of Neuroscience and Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; West China School of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
  • 9 Departments of Neuroscience and Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
  • 10 Department of Endodontics, University of Texas Health Science Center, San Antonio, TX 78229, USA. Electronic address: akopian@uthscsa.edu.
  • 11 Departments of Neuroscience and Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: xdong2@jhmi.edu.
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 potentiates TRPA1 activity in a TRPV1-dependent manner. Mechanistically, Tmem100 weakens the association of TRPA1 and TRPV1, thereby releasing the inhibition of TRPA1 by TRPV1. A Tmem100 mutant, Tmem100-3Q, exerts the opposite effect; i.e., it enhances 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-dependent modulation of the TRPA1-V1 complex, and Tmem100-3Q CPP is a promising pain therapy.

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