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 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.
authors: 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.
authors: Hao-Jui
authors: HJ
authors: Weng
authors: Departments of Neuroscience and Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors: Kush N
authors: KN
authors: Patel
authors: Department of Physiology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors: Nathaniel A
authors: NA
authors: Jeske
authors: Department of Physiology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors: Sonya M
authors: SM
authors: Bierbower
authors: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors: Wangyuan
authors: W
authors: Zou
authors: Department of Anesthesiology and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors: Vinod
authors: V
authors: Tiwari
authors: Departments of Neuroscience and Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors: Qin
authors: Q
authors: Zheng
authors: Nanjing University of Chinese Medicine, Nanjing 210046, China.
authors: Zongxiang
authors: Z
authors: Tang
authors: Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors: Gary C H
authors: GC
authors: Mo
authors: 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.
authors: Yan
authors: Y
authors: Wang
authors: Departments of Neuroscience and Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors: Yixun
authors: Y
authors: Geng
authors: 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.
authors: Jin
authors: J
authors: Zhang
authors: Department of Anesthesiology and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors: Yun
authors: Y
authors: Guan
authors: Department of Endodontics, University of Texas Health Science Center, San Antonio, TX 78229, USA. Electronic address: akopian@uthscsa.edu.
authors: Armen N
authors: AN
authors: Akopian
authors: 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.
authors: Xinzhong
authors: X
authors: Dong
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D055592:Biophysical Phenomena / Q000187:drug effects / Q000235:genetics; D016466:CHO Cells; D002211:Capsaicin / Q000633:toxicity; D002478:Cells, Cultured; D003412:Cricetulus; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D010147:Pain Measurement; D010812:Physical Stimulation; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C556658:Tmem100 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D002211:Capsaicin
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