The transmembrane channel-like 6 (TMC6) in primary sensory neurons involving thermal sensation via modulating M channels

Yating An; Jingyi Hu; Han Hao; Weixin Zhao; Xiaoxue Zhang; Jicheng Shao; Caixue Wang; Xinmeng Li; Chao Liu; Jinsha He; Yiwen Zhao; Hailin Zhang; Xiaona Du

doi:10.3389/fphar.2024.1330167

The transmembrane channel-like 6 (TMC6) in primary sensory neurons involving thermal sensation via modulating M channels

Front Pharmacol. 2024 Feb 19:15:1330167. doi: 10.3389/fphar.2024.1330167. eCollection 2024.

Authors

Yating An¹, Jingyi Hu¹, Han Hao¹, Weixin Zhao¹, Xiaoxue Zhang¹, Jicheng Shao¹, Caixue Wang², Xinmeng Li¹, Chao Liu³, Jinsha He¹, Yiwen Zhao¹, Hailin Zhang¹, Xiaona Du¹

Affiliations

¹ Department of Pharmacology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, The Hebei Collaboration Innovation Center for Mechanism, Diagnosis and Treatment of Neurological and Psychiatric Disease, Hebei Medical University, Shijiazhuang, Hebei, China.
² The Forth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
³ The Key Laboratory of Experimental Animal, Department of Animal Care, Hebei Medical University, Shijiazhuang, Hebei, China.

Abstract

Introduction: The transmembrane channel-like (TMC) protein family contains eight members, TMC1-TMC8. Among these members, only TMC1 and TMC2 have been intensively studied. They are expressed in cochlear hair cells and are crucial for auditory sensations. TMC6 and TMC8 contribute to epidermodysplasia verruciformis, and predispose individuals to human papilloma virus. However, the impact of TMC on peripheral sensation pain has not been previously investigated. Methods: RNAscope was employed to detect the distribution of TMC6 mRNA in DRG neurons. Electrophysiological recordings were conducted to investigate the effects of TMC6 on neuronal characteristics and M channel activity. Zn²⁺ indicators were utilized to detect the zinc concentration in DRG tissues and dissociated neurons. A series of behavioural tests were performed to assess thermal and mechanical sensation in mice under both physiological and pathological conditions. Results and Discussion: We demonstrated that TMC6 is mainly expressed in small and medium dorsal root ganglion (DRG) neurons and is involved in peripheral heat nociception. Deletion of TMC6 in DRG neurons hyperpolarizes the resting membrane potential and inhibits neuronal excitability. Additionally, the function of the M channel is enhanced in TMC6 deletion DRG neurons owing to the increased quantity of free zinc in neurons. Indeed, heat and mechanical hyperalgesia in chronic pain are alleviated in TMC6 knockout mice, particularly in the case of heat hyperalgesia. This suggests that TMC6 in the small and medium DRG neurons may be a potential target for chronic pain treatment.

Keywords: M channel; TMC6; chronic pain; dorsal root ganglion; heat hyperalgesia.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Natural Science Foundation of China (U21A20359) grants and Science Fund for Creative Research Groups of Natural Science Foundation of Hebei Province (no. H2020206474) to XD; the National Natural Science Foundation of China (81871075, 82071533) grants to HZ; the National Natural Science Foundation of Hebei Province (no. H2022206174) to WZ; Young Top-notch Talent Project of Hebei Provincial Education Department (BJK2024005) to WZ; the Natural Science Foundation of Hebei Province (H2023206361) to HH; the Youth Fund Project of Hebei Provincial Education Department (QN2024011) to HH.