TMC7 functions as a suppressor of Piezo2 in primary sensory neurons blunting peripheral mechanotransduction

• Published in: Cell reports (Cambridge) Vol. 43; no. 4; p. 114014
• Main Authors: Zhang, Xiaoxue, Shao, Jichen, Wang, Caixue, Liu, Chao, Hao, Han, Li, Xinmeng, An, Yating, He, Jinsha, Zhao, Weixin, Zhao, Yiwen, Kong, Youzhen, Jia, Zhanfeng, Wan, Shaopo, Yuan, Yi, Zhang, Huiran, Zhang, Hailin, Du, Xiaona
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.04.2024; Elsevier
• Subjects: Actins - metabolism; Animals; CP: Molecular biology; CP: Neuroscience; cytoskeleton; DRG; Ganglia, Spinal - metabolism; HEK293 Cells; Humans; Ion Channels - genetics; Ion Channels - metabolism; mechanosensation; Mechanotransduction, Cellular; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Piezo2; Sensory Receptor Cells - metabolism; TMC7; cytoskeleton; CP: Neuroscience; DRG; CP: Molecular biology; TMC7; Piezo2; mechanosensation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114014

The transmembrane channel-like (TMC) protein family comprises eight members, with TMC1 and TMC2 being extensively studied. This study demonstrates substantial co-expression of TMC7 with the mechanosensitive channel Piezo2 in somatosensory neurons. Genetic deletion of TMC7 in primary sensory ganglia neurons in vivo enhances sensitivity in both physiological and pathological mechanosensory transduction. This deletion leads to an increase in proportion of rapidly adapting (RA) currents conducted by Piezo2 in dorsal root ganglion (DRG) neurons and accelerates RA deactivation kinetics. In HEK293 cells expressing both proteins, TMC7 significantly suppresses the current amplitudes of co-expressed Piezo2. Our findings reveal that TMC7 and Piezo2 exhibit physical interactions, and both proteins also physically interact with cytoskeletal β-actin. We hypothesize that TMC7 functions as an inhibitory modulator of Piezo2 in DRG neurons, either through direct inhibition or by disrupting the transmission of mechanical forces from the cytoskeleton to the channel. [Display omitted] •TMC7 is expressed in DRG neurons•TMC7 deletion in DRG neurons in vivo enhances sensory mechanotransduction•Piezo2 channel expressed in DRG neurons can be modulated by TMC7•TMC7 protein physically interacts with Piezo2 and functions as a suppressor of Piezo2 Zhang et al. report that TMC7 is co-expressed with Piezo2 in somatosensory neurons. TMC7 functions as a suppressor of Piezo2 through direct interaction with the channel. Deletion of TMC7 enhances physiological and pathological sensory mechanotransduction, suggesting that TMC7 could serve as a potential therapeutic target for alleviating pathological pain.