Eric Mulhall

nature.comThe molecular basis of force selectivity by PIEZO2 - NaturePIEZO2 is intrinsically more rigid than PIEZO1, and disparate mechanical stimuli paradoxically evoke opposite conformational and gating responses in each channel.

Very excited to share our new manuscript – published today! Why are PIEZO1 and PIEZO2 are tuned to transduce different types of mechanical force? I was lucky to work with some extraordinary colleagues to begin to figure out why. www.nature.com/articles/s41... An overview of the results below ⬇️ ⬇️

FLNB also co-localizes within just tens of nanometers of PIEZO2 in sensory end organs in the skin that mediate the sense of innocuous touch, and modulates PIEZO2 function in sensory neurons. This suggests that this tethering has a prominent role in somatosensation - an area of active investigation!

A huge shoutout to co-authors Oleg Yarishkin (electrophysiologist extraordinaire), @rose-hill.bsky.social (neurophysiologist extraordinaire), Anna Koster (biochemist extraordinaire), and @ardemp.bskyverified.social (advisor extraordinaire).

We found that PIEZO2 is linked to the actin cytoskeleton and senses deflection of the lipid bilayer relative to this connection. Via proteomics and an siRNA knockdown screen, we found that the scaffolding protein Filamin B (FLNB) is required for connecting PIEZO2 to actin.

FLNB confers both selectivity and sensitivity for indentation forces specifically to PIEZO2. Without this tether, PIEZO2 freely diffuses in the membrane and becomes a stretch-sensitive channel - a kind of high-threshold version of PIEZO1.

We first found that the structure of PIEZO2 is more rigid than PIEZO1. This explains why it takes more force to activate PIEZO2 when it is just sitting by itself in the plasma membrane. This was very exciting because it was the very first result - and the answer was just so obvious!

When we tensed and slackened the plasma membrane of cells, we found that each stimulus evoked exactly the opposite conformational and gating responses in each channel! This suggested each PIEZO has a very different gating mechanism.

PIEZO1 is widely expressed throughout the body and is primarily gated by membrane tension. PIEZO2 is mainly expressed in somatosensory neurons and is preferentially activated by and is more sensitive to cellular indentation.

To figure out why they are different, we needed to look at how they respond to mechanical force in a native cellular environment. To do that, we used @abberior.rocks MINFLUX, a special type of super-resolution microscopy with nanometer precision (invented in the lab of @stefanhelllabs.bsky.social).