A Minimal Protein Region Required for the Chemical Activation of the Mechanosensitive Channel Piezo1

Abstract

The homologous Piezo1 and Piezo2 mechanosensitive ion channels are central to many important mechanotransduction processes in both normal and pathological states. Selectively targeting each Piezo homolog with pharmacological agents represents a promising avenue to probe their individual biological contribution and to treat diseases associated with Piezo channel dysfunctions. The small molecule Yoda1, which activates Piezo1 but does not affect Piezo2, is the only known molecular modulator exhibiting selectivity among mammalian Piezo channels. To date, the molecular basis for this selectivity is unknown. Here, a library of chimeras was created by replacing various protein regions from mouse Piezo1 by their homologous counterpart from mouse Piezo2. The characterization of these chimeras by calcium imaging and pressure-clamp electrophysiology led to the identification of a minimal Piezo1 region responsible for the chemical activation of Piezo1 by Yoda1. This work paves the way to elucidate the mechanisms underlying chemical activation of Piezo channels and will help expand the list of selective small molecule modulators targeting the small Piezo channel family.