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

Hao-Jui Weng; Kush N Patel; Nathaniel A Jeske; Sonya M Bierbower; Wangyuan Zou; Vinod Tiwari; Qin Zheng; Zongxiang Tang; Gary C H Mo; Yan Wang; Yixun Geng; Jin Zhang; Yun Guan; Armen N Akopian; Xinzhong Dong

doi:10.1016/j.neuron.2014.12.065

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. Epub 2015 Jan 29.

Authors

Hao-Jui Weng¹, Kush N Patel², Nathaniel A Jeske³, Sonya M Bierbower³, Wangyuan Zou⁴, Vinod Tiwari⁵, Qin Zheng², Zongxiang Tang⁶, Gary C H Mo⁷, Yan Wang⁸, Yixun Geng², Jin Zhang⁹, Yun Guan⁵, Armen N Akopian¹⁰, Xinzhong Dong¹¹

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / drug effects
Action Potentials / genetics
Animals
Biophysical Phenomena / drug effects
Biophysical Phenomena / genetics
CHO Cells
Capsaicin / toxicity
Cells, Cultured
Cricetulus
Disease Models, Animal
Electric Stimulation
Ganglia, Spinal / cytology
Ganglia, Spinal / metabolism
HEK293 Cells
Humans
Hyperalgesia / genetics
Hyperalgesia / metabolism
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neurons / drug effects
Neurons / physiology
Pain / chemically induced
Pain / metabolism*
Pain / pathology
Pain Measurement
Physical Stimulation
TRPA1 Cation Channel
TRPV Cation Channels / metabolism*
Transient Receptor Potential Channels / metabolism*

Substances

Membrane Proteins
TRPA1 Cation Channel
TRPV Cation Channels
TRPV1 protein, mouse
Tmem100 protein, mouse
Transient Receptor Potential Channels
Trpa1 protein, mouse
Capsaicin

Abstract

Publication types

MeSH terms

Substances

Grants and funding