Piezo2 voltage-block regulates mechanical pain sensitivity

Abstract

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.

Mechanosensitive PIEZO2 channels shape coronary artery development

“…Our functional analysis demonstrated that Piezo2 positive endothelial cells possess fast mechanosensitive currents that have sensitivities and kinetics similar to Piezo2dependent currents in sensory cells 63,68,73 . However, many cardiac endothelial cells that had never expressed Piezo2 also exhibited mechanosensitive currents (Fig.…”

“…5 a -g). Human pathogenic gain-of-function mutations in PIEZO2, documented in human patients 35,39,72 , dramatically increase the channels' sensitivity to mechanical force 73 . By introducing this gain of function mutation into mice we show here that PIEZO2 hypersensitivity can also lead to a disruption of heart development (Fig.…”

“…Rare PIEZO2 gain-of-function pathogenic variants in humans are associated with neurodevelopmental disorders such as Gordon syndrome and Marden-Walker syndrome as well as Distal Arthrogryposis 35,36,[38][39][40]72 . We generated mice carrying a pathogenic homozygous gain-of-function mutation (Piezo2 R2756H/R2756H ) that dramatically sensitizes the activation of endogenous PIEZO2 channels by relieving voltage block of the channel 73 . Homozygous Piezo2 R2756H/R2756H mutants are viable and so we examined the hearts of these animals at 20 weeks of age post-mortem (Fig.…”

Mechanisms of PIEZO Channel Inactivation

“…The size rather than the charge of the residue seems to yield the effect, as R2482K or R2482Q both slow down inactivation significantly (Moroni et al, 2018) [11]. In addition, the effect of R2482 is conserved in PIEZO2 as mutating the homologous mouse PIEZO2 R2756 to histidine (R2756H) or lysine (R2756K) slows down the inactivation of a PIEZO1/PIEZO2 chimera [34]. On the other hand, neutralizing the positive charge on K2479 by mutating it to glutamine (K2479Q) or reverting the charge by mutating it to glutamic acid (K2479E) abolished the voltage dependence of PIEZO1 inactivation [11].…”

“…The C-terminus of the protein is composed of an extracellular cap domain, the pore-forming inner transmembrane helix (IH) and outer transmembrane helix (OH), and an intracellular C-terminal domain. Both PIEZO1 and PIEZO2 possess voltage-dependent inactivation [27][28][29][30][31][32][33][34]. The whole-cell patch clamp with indentation shows a more rapid inactivation for PIEZO2, which has an inactivation time constant of around 5 ms compared to PIEZO1 of around 15 ms at a holding potential of −80 mV [29,35].…”