Intrinsically disordered intracellular domains control key features of the mechanically-gated ion channel PIEZO2

Clement Verkest,Juri M Jegelka,Irina Schaefer,Na Wang,Timo A Nees,Francisco J Taberner,Stefan G Lechner

doi:10.1038/s41467-022-28974-6

Abstract

A central question in mechanobiology is how mechanical forces acting in or on cells are transmitted to mechanically-gated PIEZO channels that convert these forces into biochemical signals. Here we examined the role of the intracellular domains of PIEZO2, which account for 25% of the channel, and demonstrate that these domains fine-tune properties such as poking and stretch-sensitivity, velocity coding and single channel conductance. Moreover, we show that the intrinsically disordered linker between the transmembrane helices twelve and thirteen (IDR5) is required for the activation of PIEZO2 by cytoskeleton-transmitted forces. The deletion of IDR5 abolishes PIEZO2-mediated inhibition of neurite outgrowth, while it only partially affected its sensitivity to cell indentation and does not alter its stretch sensitivity. Thus, we propose that PIEZO2 is a polymodal mechanosensor that detects different types of mechanical stimuli via different force transmission pathways, which highlights the importance of utilizing multiple complementary assays when investigating PIEZO function.

Highlights

A central question in mechanobiology is how mechanical forces acting in or on cells are transmitted to mechanically-gated PIEZO channels that convert these forces into biochemical signals
While our study eventually focused on the role of IDR5delmediated currents exhibited dramatically reduced amplitudes (IDR5), the initial characterization demonstrated that IDR2, -3 and -4 are involved in fine-tuning the function of PIEZO2
Rugiero and colleagues, who had described the velocity sensitivity of the rapidlyadapting mechanotransduction current in dorsal root ganglion neurons, which was later shown to be mediated by PIEZO2, proposed that the velocity-dependence of LTMRs might result from the rapid inactivation of the channel[43]

Summary

Introduction

A central question in mechanobiology is how mechanical forces acting in or on cells are transmitted to mechanically-gated PIEZO channels that convert these forces into biochemical signals. Most cells are equipped with sensors that enable them to detect and convert mechanical stimuli into biochemical signals – a process called mechanotransduction – that trigger adaptive processes required to maintain cell, tissue and not least body integrity in an ever-changing mechanical environment Since their discovery in 20101, the mechanically activated ion channels PIEZO1 and PIEZO2 were shown to be of crucial importance for mechanotransduction in a variety of tissues. Some of the intracellular domains are partly encoded by alternatively spiced exons[39], which highlights a possible role in fine-tuning PIEZO2 splice variant function Considering their size and localization, the intracellular domains are ideally suited to mediate possible interactions between the cytoskeleton and the channel that might be involved PIEZO2 gating

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