Ankyrin Is An Intracellular Tether for TMC Mechanotransduction Channels

Yi-Quan Tang,Sol Ah Lee,Mizanur Rahman,Siva A Vanapalli,Hang Lu,William R Schafer

doi:10.1016/j.neuron.2020.03.026

Abstract

SummaryMechanotransduction channels have been proposed as force sensors in various physiological processes, such as hearing and touch. In particular, TMC1 has been shown to constitute the pore of hair cell mechanotransduction channels, but little is known about how force is sensed by TMC channels. Here, we identify UNC-44/ankyrin as an essential component of the TMC-1 mechanotransduction channel complex in the sensory cilia of Caenorhabditis elegans mechanoreceptor neurons. Ankyrin binds indirectly to TMC-1 via evolutionarily conserved CIB proteins, which are required for TMC-1-mediated mechanosensation in C. elegans OLQ neurons and body wall muscles. Mechanosensory activity conferred by ectopically expressed TMCs in mechanoinsensitive neurons depends on both ankyrin and CIB proteins, indicating that the ankyrin-CIB subcomplex is required for TMC mechanosensitivity. Our work indicates that ankyrin is a long-sought intracellular tether that transmits force to TMC mechanotransduction channels.

Highlights

Our senses of touch, mechanical pain, hearing, balance, and proprioception all depend on mechanically activated ion channels
Ectopic expression of C. elegans or human TMC genes in mechanoinsensitive ASK neurons generates ankyrin- and CIBdependent mechanosensory activity, indicating that the ankyrin-CIB complex confers mechanosensitivity to TMC channels. These findings indicate that ankyrin acts as an intracellular tetherto confer force-sensing properties to TMC channels via CIB proteins, allowing them to function as mechanosensors
We have identified CIB and ankyrin proteins as evolutionarily conserved components of the TMC mechanotransduction channel complex and provided evidence that the ankyrin-CIB complex is essential for TMC mechanosensory gating

Summary

Introduction

Mechanical pain, hearing, balance, and proprioception all depend on mechanically activated ion channels. Two primary models have been put forward to understand how forces gate mechanotransduction channels (Ranade et al, 2015). The tether model posits that the force is conveyed to open the channel by spring-like molecular tethers, either specialized domains of the channel subunit or accessory subunits, that bind to intracellular cytoskeletal elements and/or extracellular matrix (Ranade et al, 2015). The transduction channels are localized at the tips of the shorter stereocilia and directly gated by mechanical forces imparted by hair bundle deflection (Beurg et al, 2009; Corey and Hudspeth, 1983). Biophysical characterization of hair bundle mechanics and channel gating suggests the existence of a gating spring, an elastic element that conveys force to the transduction channel. The tip link is thought to be an essential component of the mechanotransduction apparatus in hair cells (Assad et al, 1991), there remains a debate as to whether the gating spring is formed by the tip link itself or by unknown molecules connected in series with the tip link and/or intracellular cytoskeleton

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