Dataset Information

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.

SUBMITTER: Weng HJ

PROVIDER: S-EPMC4336228 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Weng Hao-Jui HJ Patel Kush N KN Jeske Nathaniel A NA Bierbower Sonya M SM Zou Wangyuan W Tiwari Vinod V Zheng Qin Q Tang Zongxiang Z Mo Gary C H GC Wang Yan Y Geng Yixun Y Zhang Jin J Guan Yun Y Akopian Armen N AN Dong Xinzhong X

Neuron 20150129 4

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 ...[more]

PMID: 25640077

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Project description:Thermal and mechanical hypersensitivity in the injured region is a common complication. Although it is well known clinically that thermal and mechanical sensitivity of the oral mucosa is different from that of the skin, the mechanisms underlying injured pain of the oral mucosa remain poorly understood. The transient receptor potential (TRP) vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) in primary afferent neurons are known to contribute to pathological pain. Therefore, we investigated whether TRPV1 and/or TRPA1 contribute to thermal and mechanical hypersensitivity following oral mucosa or whisker pad skin incision. Strong heat and mechanical and cold hypersensitivity was caused in the buccal mucosa and whisker pad skin following incisions. On day 3 after the incisions, the number of TRPV1-immunoreactive (IR) and TRPA1-IR trigeminal ganglion (TG) neurons innervating the buccal mucosa and whisker pad skin was significantly increased, and the number of TRPV1/TRPA1-IR TG neurons innervating whisker pad skin, but not the buccal mucosa, was significantly increased. Administration of the TRPV1 antagonist, SB366791, to the incised site produced a significant suppression of heat hyperalgesia in both the buccal mucosa and whisker pad skin, as well as mechanical allodynia in the whisker pad skin. Administration of the TRPA1 antagonist, HC-030031, to the incised site suppressed mechanical allodynia and cold hyperalgesia in both the buccal mucosa and whisker pad skin, as well as heat hyperalgesia in the whisker pad skin. These findings indicate that altered expressions of TRPV1 and TRPA1 in TG neurons are involved in thermal and mechanical hypersensitivity following the buccal mucosa and whisker pad skin incision. Moreover, diverse changes in the number of TRPV1 and TRPA1 coexpressed TG neurons in whisker pad skin-incised rats may contribute to the intracellular interactions of TRPV1 and TRPA1 associated with whisker pad skin incision, whereas TRPV1 and TRPA1 expression in individual TG neurons is involved in buccal mucosa-incised pain.

Dataset Information

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

Publications

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

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