Mammalian Mechanoelectrical Transduction: Structure and Function of Force-Gated Ion Channels

Abstract

The conversion of force into an electrical cellular signal is mediated by the opening of different types of mechanosensitive ion channels (MSCs), including TREK/TRAAK K 2P channels, Piezo1/2, TMEM63/OSCA and TMC1/2. Mechanoelectrical transduction plays a key role in hearing, balance, touch, proprioception and is also implicated in the autonomic regulation of blood pressure and breathing. Thus, dysfunction of MSCs is associated with a variety of inherited and acquired disease states. Significant progress has recently been made in identifying these channels, solving their structure and understanding the gating of both hyperpolarizing and depolarizing MSCs. Besides prototypical activation by membrane tension, additional gating mechanisms involving channel curvature and/or tethered elements are at play.

Tethering Piezo channels to the actin cytoskeleton for mechanogating via the E-cadherin-β-catenin mechanotransduction complex

“…The mechanically activated Piezo channel, including Piezo1 and Piezo2 (Coste et al, 2010;Coste et al, 2012), represent a class of versatile mechanotransducers for mediating distinct forms of mechanical stimuli in a wide variety of cell types and consequently governing a broad spectrum of biological processes (Douguet and Honore, 2019;Murthy et al, 2017;Wu et al, 2016;Xiao, 2019). Elucidating its mechanogating mechanism is fundamental to understand how it might fulfill its mechanotransduction function in intact cells.…”

“…The cellular mechanotransduction process requires designated mechanotransducers to convert mechanical force into various fundamental biological activities, ranging from cellular division, differentiation and migration to physiological sensing of blood pressure, touch, mechanical pain, balance and sound (Chalfie, 2009;Douguet and Honore, 2019;Jin et al, 2020;Katta et al, 2015;Leckband and de Rooij, 2014;Lecuit and Yap, 2015;Niessen et al, 2011). Adhesion molecules and mechanosensitive ion channels represent two major types of mechanotransducers.…”

“…Mechanosensitive ion channels can respond rapidly to mechanical forces to allow ion flux via two main proposed mechanogating models: force-from-lipids and force-from-filament (Douguet and Honore, 2019;Gillespie and Walker, 2001;Jin et al, 2020;Kung et al, 2010;Markin and Hudspeth, 1995;Ranade et al, 2015). The force-from-lipids model proposes that the channel can directly respond to changes in membrane tension (Anishkin et al, 2014;Kung et al, 2010), which is exemplified by the bacteria mechanosensitive channel of large conductance (MscL) (Martinac et al, 1990;Sukharev et al, 1994) and the eukaryotic two-pore domain K + channels TREK-1 and TRAAK (Brohawn et al, 2014).…”

“…Endogenously expressed Piezo1 or Piezo2 confers exquisite mechanosensitivity to various cell types (Murthy et al, 2017;Xiao, 2019), including epithelial cells (Eisenhoffer et al, 2012;Gudipaty et al, 2017), endothelial cells (Li et al, 2014;Nonomura et al, 2018;Ranade et al, 2014a), smooth muscle cells (Retailleau et al, 2015), red blood cells (Zarychanski et al, 2012), chondrocytes (Servin-Vences et al, 2017), osteoblasts (Sun et al, 2019), merkel cells (Woo et al, 2014) and sensory neurons (Ranade et al, 2014b). Such Piezo-mediated mechanotransduction process controls a wide variety of key biological activities (Douguet and Honore, 2019;Murthy et al, 2017;Xiao, 2019), including epithelial homeostasis (Eisenhoffer et al, 2012;Gudipaty et al, 2017), vascular and lymphatic development and remodeling (Li et al, 2014;Nonomura et al, 2018;Ranade et al, 2014a), blood pressure regulation (Rode et al, 2017;Wang et al, 2016;Zeng et al, 2018), bone formation (Sun et al, 2019), and somatosensation of touch (Ranade et al, 2014b;Woo et al, 2014), balance (Woo et al, 2015), tactile pain Szczot et al, 2018) and breathing (Nonomura et al, 2017). Abnormal Piezo channel functions arising from genetic mutations have been associated with many human genetic diseases, including Piezo1-based dehydrated hereditary stomatocytosis (Zarychanski et al, 2012) and familial generalized lymphatic dysplasia (Fotiou et al, 2015;Lukacs et al, 2015), and Piezo2-based distal arthrogryposis <...>…”

Polynuclear ruthenium amines inhibit K2P channels via a ‘finger in the dam’ mechanism

“…K2P2.1 (TREK-1) is the founding member of the thermo-and mechanosensitive subgroup of K2Ps (Douguet and Honore, 2019;Feliciangeli et al, 2014). Although this channel is resistant to RuR inhibition ( Figure 1B and D, Table 1) (Braun et al, 2015), two electrode voltage clamp (TEVC) recordings in Xenopus oocytes of outward current inhibition by RuR under physiological ionic conditions showed that installation of a point mutation I110D at the base of the K2P2.1 (TREK-1) CAP domain conferred sub-micromolar RuR sensitivity to K2P2.1 (TREK-1) (IC50 = 0.287 ± 0.054 µM)(Figs.…”