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Piezo2 voltage-block regulates mechanical pain sensitivity

PIEZO2 mechanosensitive channels are required for normal touch sensation. However, PIEZO2 channels are almost completely blocked at negative resting membrane potentials. We show that PIEZO2 voltage-block can be relieved by mutations at a conserved Arginine (R2756) which dramatically sensitizes the channel to mechanical stimuli. We generated Piezo2R2756H/R2756H and Piezo2R2756K/R2756K knock-in mice to ask how voltage regulates the endogenous mechanosensitivity of sensory neurons. Surprisingly, mechanosensitive currents in nociceptors, neurons that detect noxious mechanical stimuli, were substantially sensitized in Piezo2 knock-in mice, but touch receptors were largely unaffected. Piezo2 knock-in mice were hypersensitive to noxious mechanical stimuli as their nociceptors acquired properties similar to ultrasensitive touch receptors. Thus, mechanical pain sensitivity can be tuned by voltage-block of PIEZO2 channels, a channel property potentially amenable for pharmacological modulation.