Force From Filaments: The Role of the Cytoskeleton and Extracellular Matrix in the Gating of Mechanosensitive Channels

Abstract

The senses of proprioception, touch, hearing, and blood pressure on mechanosensitive ion channels that transduce mechanical stimuli with high sensitivity and speed. This conversion process is usually called mechanotransduction. From nematode MEC-4/10 to mammalian PIEZO1/2, mechanosensitive ion channels have evolved into several protein families that use variant gating models to convert different forms of mechanical force into electrical signals. In addition to the model of channel gating by stretching from lipid bilayers, another potent model is the opening of channels by force tethering: a membrane-bound channel is elastically tethered directly or indirectly between the cytoskeleton and the extracellular molecules, and the tethering molecules convey force to change the channel structure into an activation form. In general, the mechanical stimulation forces the extracellular structure to move relative to the cytoskeleton, deforming the most compliant component in the system that serves as a gating spring. Here we review recent studies focusing on the ion channel mechanically activated by a tethering force, the mechanotransduction-involved cytoskeletal protein, and the extracellular matrix. The mechanosensitive channel PIEZO2, DEG/ENaC family proteins such as acid-sensing ion channels, and transient receptor potential family members such as NompC are discussed. State-of-the-art techniques, such as polydimethylsiloxane indentation, the pillar array, and micropipette-guided ultrasound stimulation, which are beneficial tools for exploring the tether model, are also discussed.

Mechanosensitive Ion Channels and Their Role in Cancer Cells

“…A similar phenomenon has also been described for eukaryotic channels such as two-pore domain potassium channels TREK-1 and TRAAK, TRPV4, and Piezo1 [ 31 , 32 , 33 , 34 ]. In the force-from-filaments model a membrane-bound channel is elastically tethered between the cytoskeleton and the extracellular molecules, and force-induced displacement of these tethers opens the channel [ 35 ]. This type of activation is hypothesized for some members of the TRP and ASIC family and Piezo2 [ 36 , 37 , 38 ].…”

“…Two models of mechanosensitive ion channel gating have been established. ( A ) In the force-from-lipids model, alterations in lipid organization lead to channel activation; ( B ) In the force-from-filaments model, the causative factors are changes in the extracellular matrix and cytoskeleton [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ].…”

Keratinocyte Piezo1 drives paclitaxel-induced mechanical hypersensitivity

“…Paclitaxel is a chemotherapeutic due to its ability to stop tumor proliferation, a task it completes by stabilizing microtubules and reducing cytoskeletal dynamics 19 . Recent research has highlighted the role of the cytoskeleton in the mechanical sensitivity of both Piezo1 and Piezo2 20 . Therefore, we hypothesized that paclitaxel-induced sensitization of Piezo1 may result from microtubule stabilization.…”

Unraveling the Dual-Stretch-Mode Impact on Tension Gauge Tethers’ Mechanical Stability

“…This characteristic holds promise for a variety of applications. In addition to shedding light on the time scales involved in specific mechanotransduction processes at cell–matrix adhesions, − cell–cell adherence junctions, and mechanical activation of T-cells, , they may also be applied to study the tension duration of various mechanically sensitive membrane receptors, such as adhesion GPCRs , and tethered ion channels . Moreover, the potential of dual-stretch-mode TGTs to significantly augment the utility of TGTs as mechanical instruments in DNA nanotechnology and bioengineering is considerable.…”