Piezo proteins are pore-forming subunits of mechanically activated channels

Coste, Bertrand; Xiao, Bailong; Santos, Jose S.; Syeda, Ruhma; Grandl, Jörg; Spencer, Kathryn S. R.; Kim, Sung Eun; Schmidt, Manuela; Mathur, Jayanti; Dubin, Adrienne E.; Montal, Mauricio; Patapoutian, Ardem

doi:10.1038/nature10812

Cited by 948 publications

(936 citation statements)

References 37 publications

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“…Importantly, using bilayer reconstitution experiments, it was further shown that Piezo proteins are pore-forming subunits [26]. The function of Drosophila Piezo has recently been shown in mechanical nociception, in line with the role of mouse Piezo2 in pain-sensitive dorsal root ganglion neurons [25,27].…”

Section: Introductionmentioning

confidence: 77%

Piezo1‐dependent stretch‐activated channels are inhibited by Polycystin‐2 in renal tubular epithelial cells

et al. 2013

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Mechanical forces associated with fluid flow and/or circumferential stretch are sensed by renal epithelial cells and contribute to both adaptive or disease states. Non-selective stretch-activated ion channels (SACs), characterized by a lack of inactivation and a remarkably slow deactivation, are active at the basolateral side of renal proximal convoluted tubules. Knockdown of Piezo1 strongly reduces SAC activity in proximal convoluted tubule epithelial cells. Similarly, overexpression of Polycystin-2 (PC2) or, to a greater extent its pathogenic mutant PC2-740X, impairs native SACs. Moreover, PC2 inhibits exogenous Piezo1 SAC activity. PC2 coimmunoprecipitates with Piezo1 and deletion of its N-terminal domain prevents both this interaction and inhibition of SAC activity. These findings indicate that renal SACs depend on Piezo1, but are critically conditioned by PC2.

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Section: Introductionmentioning

confidence: 77%

Piezo1‐dependent stretch‐activated channels are inhibited by Polycystin‐2 in renal tubular epithelial cells

et al. 2013

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“…As mechanotransductory channels, PIEZO channels form a close functional unit with the plasma membrane (43)(44)(45), also demonstrated by the inhibitory effect of GsMTx4, which acts as a gating modifier that inserts at the channel-lipid interface (32). Against this background, we decided to next test the function of dynamin, recently referred to as "membrane remodeler" (46), on PIEZO mechanotransductory function in chondrocytes.…”

Section: Resultsmentioning

confidence: 99%

Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage

Lee¹,

Leddy²,

Chen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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367

348

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Diarthrodial joints are essential for load bearing and locomotion. Physiologically, articular cartilage sustains millions of cycles of mechanical loading. Chondrocytes, the cells in cartilage, regulate their metabolic activities in response to mechanical loading. Pathological mechanical stress can lead to maladaptive cellular responses and subsequent cartilage degeneration. We sought to deconstruct chondrocyte mechanotransduction by identifying mechanosensitive ion channels functioning at injurious levels of strain. We detected robust expression of the recently identified mechanosensitive channels, PIEZO1 and PIEZO2. Combined directed expression of Piezo1 and -2 sustained potentiated mechanically induced Ca 2+ signals and electrical currents compared with single-Piezo expression. In primary articular chondrocytes, mechanically evoked Ca 2+ transients produced by atomic force microscopy were inhibited by GsMTx4, a PIEZO-blocking peptide, and by Piezo1-or Piezo2-specific siRNA. We complemented the cellular approach with an explant-cartilage injury model. GsMTx4 reduced chondrocyte death after mechanical injury, suggesting a possible therapy for reducing cartilage injury and posttraumatic osteoarthritis by attenuating Piezo-mediated cartilage mechanotransduction of injurious strains.A rticular cartilage is a hydrated connective tissue that supports loads and minimizes friction in the diarthrodial joints. It has a highly differentiated extracellular matrix (ECM) composed primarily of type II collagen, the large aggregating proteoglycan, aggrecan, and water. Chondrocytes are the only cells in cartilage and are responsible for maintaining and remodeling cartilage through a homeostatic balance of anabolic and catabolic activities. Under normal physiologic conditions, chondrocytes are exposed to millions of cycles of mechanical loading per year (1). These mechanical signals play an important role in regulating chondrocyte anabolic and biosynthetic activity, as evidenced by cartilage atrophy following periods of disuse or immobilization (2-7). However, under abnormal loading conditions (e.g., due to obesity, trauma, or joint instability), mechanical factors play a critical role in the onset and progression of osteoarthritis (1). Such "injurious" loading has been modeled in vitro using explant culture systems that replicate many of the early cellular and molecular events characteristic of osteoarthritis (8). Osteoarthritis is a painful and debilitating disease of weight-bearing joints that affects over 26 million people in the United States (9) with posttraumatic arthritis being responsible for ∼12% of the incidence of osteoarthritis (10).Despite the critical importance of mechanical loading in health and disease of synovial joints, the mechanisms of mechanotransduction of chondrocytes are not fully understood and are likely to differ under physiologic and pathologic conditions (11)(12)(13)(14). Although many different mechanisms have been shown to be involved in chondrocyte mechanotransduction (13,(15)(16)(17), recent st...

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“…One example of how this protocol can be adapted to record one channel currents from other ions channels, specifically mouse PIEZO1, a mechanosensitive ion channel, is presented below (Figure 7) 25,26 .…”

Section: Recombinant Piezo1 Channelsmentioning

confidence: 99%

One-channel Cell-attached Patch-clamp Recording

Maki

Cummings

Paganelli

et al. 2014

JoVE

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Ion channel proteins are universal devices for fast communication across biological membranes. The temporal signature of the ionic flux they generate depends on properties intrinsic to each channel protein as well as the mechanism by which it is generated and controlled and represents an important area of current research. Information about the operational dynamics of ion channel proteins can be obtained by observing long stretches of current produced by a single molecule. Described here is a protocol for obtaining one-channel cell-attached patchclamp current recordings for a ligand gated ion channel, the NMDA receptor, expressed heterologously in HEK293 cells or natively in cortical neurons. Also provided are instructions on how to adapt the method to other ion channels of interest by presenting the example of the mechanosensitive channel PIEZO1. This method can provide data regarding the channel's conductance properties and the temporal sequence of openclosed conformations that make up the channel's activation mechanism, thus helping to understand their functions in health and disease. Video LinkThe video component of this article can be found at

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Piezo proteins are pore-forming subunits of mechanically activated channels

Cited by 948 publications

References 37 publications

Piezo1‐dependent stretch‐activated channels are inhibited by Polycystin‐2 in renal tubular epithelial cells

Piezo1‐dependent stretch‐activated channels are inhibited by Polycystin‐2 in renal tubular epithelial cells

Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage

One-channel Cell-attached Patch-clamp Recording

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