Abstract
Piezo proteins are transmembrane ion channels which transduce many forms of mechanical stimuli into electrochemical signals. Their pore, formed by the assembly of three identical subunits, opens by an unknown mechanism. Here, to probe this mechanism, we investigate the interaction of Piezo1 with the small molecule agonist Yoda1. By engineering chimeras between mouse Piezo1 and its Yoda1-insensitive paralog Piezo2, we first identify a minimal protein region required for Yoda1 sensitivity. We next study the effect of Yoda1 on heterotrimeric Piezo1 channels harboring wild type subunits and Yoda1-insensitive mutant subunits. Using calcium imaging and patch-clamp electrophysiology, we show that hybrid channels harboring as few as one Yoda1-sensitive subunit exhibit Yoda1 sensitivity undistinguishable from homotrimeric wild type channels. Our results show that the Piezo1 pore remains fully open if only one subunit remains activated. This study sheds light on the gating and pharmacological mechanisms of a member of the Piezo channel family.
Highlights
Piezo proteins are transmembrane ion channels which transduce many forms of mechanical stimuli into electrochemical signals
The recently identified mechanosensitive ion channels Piezo[1] and Piezo[2] participate in a bewildering number of mechanotransduction processes[1]. These include touch sensation[2,3,4], proprioception[5], hearing[6], vascular[7,8] and brain development[9], blood flow sensing[10], osmotic homeostasis[11], and epithelial cell number regulation[12,13]. In light of their physiological importance, both gain-of-function and loss-of-function mutations of Piezo channels have been associated with pathological conditions such as xerocytosis[11,14,15,16], arthrogryposis[17,18,19,20,21,22,23], and lymphedema[24]
The identification of specific protein regions involved in mechanosensing is emerging[33], the mechanism by which mechanical forces are detected by Piezo channels and transmitted to the pore is currently unclear
Summary
Piezo proteins are transmembrane ion channels which transduce many forms of mechanical stimuli into electrochemical signals. Their pore, formed by the assembly of three identical subunits, opens by an unknown mechanism. The recently identified mechanosensitive ion channels Piezo[1] and Piezo[2] participate in a bewildering number of mechanotransduction processes[1] These include touch sensation[2,3,4], proprioception[5], hearing[6], vascular[7,8] and brain development[9], blood flow sensing[10], osmotic homeostasis[11], and epithelial cell number regulation[12,13]. Our analysis indicates that the presence of a single agonistsensitive subunit per channel is sufficient to mediate Yoda1induced pore opening
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