Pain resulting from strong mechanical stimuli poses significant challenges for

effective management. However, the molecular mechanisms underlying acute

mechanical pain remain elusive. This study identifies Tentonin 1/TMEM150A

(TTN1) as a pore-forming mechanosensory channel in sensory Schwann cells

(SSCs) known to be associated with free nerve endings in the epidermis. TTN1 is

expressed in epidermal processes of SSCs. Isolated SSCs are mechanosensitive

but not responsive to noxious heat, cold or capsaicin. Moreover, Ttn1-cKO mice

displayed markedly diminished responses to various acute and chronic

mechanical pain conditions. Optogenetic stimulation of TTN1-expressing cells

induced nocifensive behaviors, whereas overexpression of Ttn1 in Ttn1-cKO mice

restored impaired mechanical pain. A conotoxin mutant, NMB-1, inhibited TTN1

and evoked analgesic effects in acute mechanical pain. We conclude that TTN1 is

a molecular component for mediating mechanical pain in the periphery, which

proposes its potential as a therapeutic target for treating diverse pain conditions.