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Many fundamental biological processes such as the sense of touch and pain and the regulation of vascular development and blood pressure require designated mechanotransducers for converting mechanical force into electrochemical signals, a process termed mechanotransduction. Mechanically activated (MA) cation channels represent a specialized type of mechanotransducers for rapidly responding to changes of mechanical force to either excite cell membranes or trigger biochemical signaling. However, the molecular identities and mechanogating mechanisms of mammalian MA cation channels remain largely unknown, which has rendered mechanotransduction much less understood compared to our understanding of chemotransduction mediated by ligand-gated ion channels and electrotransduction mediated by voltage-gated ion channels. Following the discovery and establishment of the MA Piezo channel family, we have been utilizing Piezo1 and Piezo2 as prototypes of mammalian MA cation channels to understand how Piezo channels effectively convert mechanical force into selective cation permeation at an atomic-level of spatial resolution, a millisecond-level of temporal resolution, a picoampere-level of current resolution and a piconewton level of force resolution, and how their mechanosensitivity and ion permeation properties precisely control various mechanotransduction processes at both cellular and animal levels. Our ultimate goal is to harness the deep understanding of Piezo channels for developing novel therapeutics for disease treatment or novel technologies for biological manipulation. Toward these research aims, we have established a multidisciplinary research platform covering molecular biology, biochemistry, structural biology, cell biology, patch-clamp electrophysiology, high-throughput drug screening and mouse and human genetics, and made significant progress in understanding the structure-function relationship and physiological and pharmacological regulations of Piezo channels.

• Determined the cryo-EM structures of the full-length mouse Piezo1, a novel Piezo1 isoform-Piezo1.1 identified by my lab, and Piezo2, revealing their unique structural features and providing structural blueprints for uncovering their ion permeation, mechanogating and regulatory mechanisms (Nature 2015; Nature 2018; Nature 2019; Neuron 2020).

• Identified the bona fide pore with three intracellular lateral portal-based ion-conducting routes, the transmembrane gate, the intracellular lateral plug gates, and key pore property-determining residues, elucidating the ion permeation mechanism (Neuron 2016; Neuron 2020).

• Identified key mechanogating components and pathways and proposed the plug-and-latch gating, dual-gating and lever-like gating models for underlying the mechanogating mechanisms of Piezo channels (Nature 2018; Nature Communications 2018; Neuron 2020).

• Identified Piezo interacting proteins and alternative splicing variants, providing insight into physiological regulatory mechanisms (Nature Communications 2017; Neuron 2020; BioRxiv 2020).

• Identified Piezo1 activators Jedi1 and Jedi2 via establishing a high-throughput drug-screening platform and revealed their activation mechanism (Nature Communications 2018).

• Explored the role of Piezo channels in determining the physiological and pathophysiological processes of touch and pain sensation, bone formation and heart function (Cell Reports 2019; eLife 2019; Nature Communications 2021).

• Demonstrated that STIM1 functions as an in vivo warm sensor in keratinocytes to define the optimal preference temperature (OPT), which might be utilized as a peripheral reference temperature for precise warm sensation (Cell Research 2019).

Figure Structural design and mechanogating mechanisms of Piezo channels.

A, The 38-TM topology comprised of nine repetitive transmembrane helical units (THUs) of 4-TMs each, the outer helix (OH), the pore-lining inner helix (IH), and other featured domains such as the Beam, Lateral Plug, Latch, the intracellular C-terminal domain (CTD), Anchor, and the extracellular Cap. B, The extracellular view of the three bladed propeller structure. C, The side view of the nano-bowl configuration shaped by the highly curved transmembrane regions of the three blades is illustrated in the cyan bowl. The mid-plane opening diameter, depth, surface area (A_bowl) and the in-plane membrane area (Ain-plane of 450 nm²) shown in green oval are labeled.

D, Force-induced rotation of the Cap (indicated by the orange arrow) and the blades (indicated by the dark green arrows) might open the transmembrane pore and unplug the lateral plug gates to allow cation conduction via the central transmembrane pore and the three intracellular lateral portals, which are labeled in the top panel. E, When the blades become completely planar upon membrane tension application (indicated by the dark green arrows), the surface area of the nano-bowl will be expanded to a maximal in-plane membrane area of 700 nm². In the grey box, tension (γ) induced free energy change upon transition from closed to open channel is described by the free energy equation. The tension sensitivity is determined by the change of the membrane area expansion (ΔA_in-plane), which might reach a maximal value of 250 nm². The dashed and solid red arrows in the top and bottom panels respectively indicate the closed and open ion-conducting pathways. Panel D and E also illustrate the dual-gating model of Piezo channels, in which the transmembrane gate is gated by motion of the top Cap, while the lateral plug gates are coordinately unplugged via a plug-and-latch mechanism upon flattening the curved blade-membrane system. THU4 and THU5 are shown in dark green to highlight their reported role in mechanogating of Piezo1.