Within our bodies, cells and tissues are constantly being pushed and pulled by their surrounding environment. These mechanical forces are then transformed into electrical or chemical signals by cells. This process is crucial for many biological structures, such as blood vessels, to develop correctly, and is also a key part of our senses of touch and hearing.

In 2010, researchers discovered a group of ion channels—proteins embedded in the membrane that surrounds a cell—that open up when a force is applied and allow ions such as calcium, potassium, and sodium to flow. This movement of ions generates the electrical response of the cell to the applied force. However, not much is known about how these ‘Piezo’ ion channels work. To investigate this, it is important to be able to precisely control how and when the Piezo channels open. Many other ion channels are studied by using small chemical compounds to activate them, but there were none that were known to act on Piezo proteins.

Syeda et al.—including some of the researchers involved in the 2010 work—screened over three million compounds for their ability to cause calcium ions to flow into human cells to try to identify chemicals that activate the Piezo channels. This revealed one promising candidate named Yoda1, which specifically activated Piezo1: a Piezo protein that had previously been linked to a role in blood vessel development in embryos.

To investigate how Yoda1 activates Piezo1, Syeda et al. placed Piezo1 in an artificial cell membrane that did not contain any other cellular components. When Yoda1 was added to this set up, the Piezo1 channels opened up. This suggests that Piezo1 and Yoda1 interact in a manner that does not require additional cellular components other than a cell membrane.

Separate work by Cahalan, Lukacs et al. uses Yoda1 to reveal that Piezo1 helps to control the volume of red blood cells, showing that in the future, Yoda1 could be valuable in research that investigates the roles of Piezo1.

Mechanotransduction describes processes by which mechanical forces are converted into biological responses. Mechanotransduction is essential for physiological functions including the sense of touch, hearing, and blood pressure regulation. The molecular mechanisms involved in mechanotransduction have been largely unknown, but mechanically activated cation channels are postulated to play important roles (Delmas et al., 2011). Piezo1 and Piezo2 are necessary and sufficient for mechanically activated cation channel activity (Coste et al., 2010). These proteins are expressed in various mechanically sensitive cell types, and Piezo1 and Piezo2 have recently been shown to be required for vascular development and touch sensing, respectively (Li et al., 2014; Maksimovic et al., 2014; Ranade et al., 2014a; Ranade et al., 2014b; Woo et al., 2014). In humans, Piezo1 gain-of-function mutations are associated with a hereditary red blood cell condition termed dehydrated hereditary stomatocytosis, while Piezo2 gain-of-function mutations are associated with three phenotypically overlapping conditions termed distal arthrogryposis type 5, Gordon Syndrome, and Marden–Walker Syndrome (Piezo2) (Albuisson et al., 2013; Andolfo et al., 2013; Bae et al., 2013; Coste et al., 2013; McMillin et al., 2014). Piezo proteins form a distinct class of proteins with no apparent sequence similarity to other proteins and channels (Coste et al., 2010; Bae et al., 2011; Nilius and Honore, 2012). They typically consist of >2000 amino acids with ∼30–40 putative transmembrane segments, and Piezo1 has been shown to assemble as a homotetramer of ∼1.2 million daltons. Purified Piezo1 can be reconstituted in lipid bilayers resulting in spontaneous cation currents. This indicates that Piezos constitute channel-forming proteins, as opposed to accessory subunits (Coste et al., 2012). Both vertebrate and invertebrate Piezo channels can be activated by mechanical stimuli suggesting an evolutionarily conserved gating mechanism geared to transduce mechanical force (Kim et al., 2012). Indeed, to date, mechanical stimuli are the only means to activate Piezo ion channels. In comparison, temperature-activated transient receptor potential (TRP) ion channels are polymodal and are the sensors of various chemicals that cause a burning sensation such as capsaicin and mustard oil, as well as endogenous compounds that cause inflammation (Julius, 2013). Studies on the chemical activation of TRP channels have been crucial to understand the physiological role of these channels and have contributed to mechanistic appreciation of how these ion channels are gated (Jordt and Julius, 2002; Bandell et al., 2006; Macpherson et al., 2007; Cao et al., 2013; Julius, 2013). The discovery of a chemical agonist of Piezo channels could thus benefit the study of mechanotransduction.

We set out to probe Piezos for chemical-mediated activation. As Piezos are calcium-permeable channels, we hypothesized that Piezo activity could be monitored using calcium-sensitive fluorophores. We tested this by overexpressing Piezo1 in human embryonic kidney (HEK) cells and monitoring intracellular calcium in response to pressure exerted on the cell via a blunt glass probe. In Piezo1 expressing cells, a sequence of mechanical stimulations using a piezo-electric driven probe caused reversible calcium responses that increased with increasing probe displacement until ultimately an irreversible Ca²⁺ signal ensued as a consequence of membrane rupture. In contrast, control cells showed no reversible responses and only irreversible calcium flux upon cell perforation was observed. (Figure 1A). This suggested that Piezo1-mediated calcium flux could be measured via calcium fluorophores. With the objective to identify either a Piezo1 or Piezo2 agonist, we co-transfected HEK cells with mPiezo1 and mPiezo2 cDNAs and screened a collection of ∼3.25 million low molecular weight (LMW) compounds for their ability to induce calcium influx in these cells. This led us to identify a synthetic compound that elicits Ca²⁺ flux in Piezo1- but not vector-transfected cells; we named this compound Yoda1 (see ‘Materials and methods’ and Figure 1D for screen and Yoda1 details). Yoda1-induced calcium responses depended largely on calcium influx as the chelation of extracellular calcium dramatically reduced the responses, while the depletion of intracellular calcium stores using thapsigargin did not (Figure 1B). Still, calcium-chelating conditions did not completely abolish the responses, raising the possibility of some functional Piezo1 in intracellular membranes upon overexpression. Concentration-response experiments showed that Yoda1 at micromolar concentrations induced robust Ca²⁺ responses in cells transfected with either human or mouse Piezo1, but not Piezo2-transfected cells, indicating its selectivity for Piezo1 (Figure 1C). At higher Yoda1 concentrations (>∼20 μM), the solutions became increasingly opaque. Therefore, the apparent EC₅₀ is likely affected by compound insolubility and may not allow meaningful interpretation. We further tested six distinct hPiezo1 mutants that we previously identified in xerocytosis patients and which exhibited increased mechanically induced currents (Albuisson et al., 2013). Invariably, the Yoda1-induced calcium responses were bigger in cells transfected with these mutant channels than cells transfected with wild-type Piezo1, consistent with their gain-of-function phenotype (Figure 1—figure supplement 1). The effect of Yoda1 appears to critically depend on the dichloro substitution (Figure 1D), as similar compounds present in the collection lacking the chlorines were not identified in the screen (data not shown). Furthermore, the oxidation state of the thioether group appears critical as no activity could be observed with the sulfone analog (tested at ≤30 μM, data not shown).

Figure 1 with 1 supplement see all

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We next sought to assess the effect of Yoda1 on mPiezo1 channel function directly by recording mPiezo1-mediated currents, both in the presence and absence of mechanical force (Figure 2A–E). In HEK cells transiently transfected with mPiezo1, using a cell-attached patch configuration, currents were measured before and during a series of increasing negative pressures applied via the recording pipette. The presence of Yoda1 caused multiple distinct effects. Firstly, Yoda1 caused a dramatic change in the kinetics of the mechanical responses, as it notably slowed the inactivation phase of the transient currents (Figure 2A). Secondly, Yoda1 sensitized mPiezo1 to activation by pressure as indicated by a leftward shift in the current–pressure relationship, reducing the half maximal activation pressure (P50) by about 15 mm Hg (Figure 2B,C). Lastly, in the absence of negative pressure, we observed small currents in Yoda1-exposed patches. The Yoda1-dependent currents were a fraction of those attained by stretch: 9.0 ± 2.2% of the maximal attainable current compared to 1.5 ± 0.4% in control patches without Yoda1 (Figure 2B,D,E). These results suggest that Yoda1 both modifies Piezo1 mechanotransduction currents and partially activates Piezo1 in the absence of externally applied pressure (note, however, that some membrane tension exists in cell-attached patches even prior to the application of negative pressure) The partial activation of Piezo1 by Yoda1 might be due to a variety of reasons, including (1) an indirect mechanism of action (but see below), (2) an inefficacious gating mechanism (i.e., acting as a gating modifier instead of a full agonist), or (3) a very high actual EC₅₀ (see comment on insolubility above). We also tested the effect of Yoda1 (10 μM) in whole-cell configuration, where mechanical pressure can be applied using a piezoelectric-driven glass probe. This concentration did not lead to measurable mPiezo1 currents in the absence of pressure but did cause a clear slowing of the inactivation phase of the mechanically activated currents, similar to the cell-attached patch experiments (Figure 2F,G). No such change in kinetics could be observed for Piezo2 consistent with Yoda1 having a Piezo1 selective effect (Figure 2H).

Figure 2

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As discussed above, Yoda1 might act directly on Piezo1 or indirectly via other membrane or even intracellular mediators. To address this, we set out to test its effect on purified mPiezo1 reconstituted in droplet interface lipid bilayers (DIBs). Previously, we reconstituted purified mPiezo1 channels into asymmetric DIBs containing DiPhytanoyl-sn-glycero-3-PhosphoCholine (DPhPC) and 1,2-dioleoyl-sn-glycero-3-phosphate (DOPA) and observed spontaneous cation-selective channel activity (Coste et al., 2012). Here, to study mPiezo1 activation, we utilized symmetric DIBs made up of only DPhPC in which reconstituted mPiezo1 does not show constitutive activity (Figure 3A). Application of 1 μM Yoda1-induced discernable single-channel currents with a conductance similar to what we previously observed for spontaneously active mPiezo1 in asymmetric bilayers (Figure 3B). Higher Yoda1 concentrations yielded robust currents with a staircase-like appearance, indicating the presence of multiple (30–40) functional channels (Figure 3C,D).

Figure 3

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Next, we assessed single-channel parameters of mPiezo1 reconstituted in symmetric DPhPC bilayers in the presence of 1 μM Yoda1 (Figure 3E). The channel exhibited closed dwell-time distributions that fitted well to a two-component probability density function; τ_{1 closed} = 3 ± 1 ms and τ_{2 closed} = 57 ± 15 ms. The two time constants differ in duration by > 10-fold, a property of a bursting channel, where τ_{1 closed} is the closed time within a burst, and τ_{2 closed} is the closed time between bursts. The open dwell time is fitted to a single-component probability density function with characteristic mean open time τ _open = 55 ± 9 ms. Although, no direct comparison can be made for mPiezo1 parameters with and without Yoda1 (due to lack of mPiezo1 activity in symmetric bilayers without Yoda1), we analyzed single-channel properties of mPiezo1 acquired in asymmetric bilayers without Yoda1 (Figure 3F). In an asymmetric bilayer, the channel exhibited characteristic bursting pattern with two closed time distributions, τ_{1 closed} = 5 ± 1 ms, τ_{2 closed} = 47 ± 9 ms, and an open time distribution τ _open = 13 ± 4 ms. The significant difference in τ _open (13 ± 4 ms vs 55 ± 9 ms) suggests that mPiezo1 remains open for longer times in the presence of Yoda1. No significant change was observed in τ _closed, suggesting that Yoda1 mainly stabilizes the open state rather than destabilizing the closed state.

A detailed biophysical analysis will be required to understand the mechanism of action of Yoda1. Our present analysis provides the first steps towards this goal. For instance, our lipid bilayer experiments suggest that Yoda1 does not require other proteins or specific lipid domains to exert an effect on Piezo1. This suggests its effect is either directly on the channel or via long-range membrane-delimited effects, for instance through a change in membrane tension or curvature of the membrane. Indeed, compounds that modify membrane curvature are known to affect mechanically sensitive ion channels (Patel et al., 1998). However, such compounds are typically amphipaths which Yoda1 is not (Sheetz and Singer, 1974). More importantly, the effect of Yoda1 appears governed by stringent structural requirements both on the side of the chemical and on the side of the channel (as no effect on Piezo2 was observed), fitting a model in which Yoda1 directly interacts with Piezo1.

Our electrophysiological experiments in cells suggest that Yoda1 prominently affects the sensitivity and the inactivation kinetics of mechanically induced responses but at best causes a slight mPiezo1 activation in the absence of mechanical stimuli. In the bilayer system, we observed that Yoda1 stabilizes the open channel, potentially explaining the slowing of mPiezo1 inactivation kinetics observed in cells. However, we also observe prominent Yoda1-dependent calcium responses in cell culture and currents in artificial bilayers in the absence of externally applied forces. Therefore, the discrepancy in various levels of channel activity observed with different assays used here remains unexplained, and future in-depth understanding of mechanism of Yoda1 action on Piezo1 might shed light on these apparently disparate observations. Regardless, we show in an accompanying paper that Yoda1 causes Piezo1-dependent red blood cell dehydration, arguing for sufficient activation of the ion channel in the absence of external forces to cause a robust physiological impact.

Irrespective of whether Yoda1 acts as a full activator or as a positive modulator, our results suggest that we have identified the first Piezo1 agonist. This finding is important from two perspectives. Firstly, our studies provide the first evidence of non-mechanical activation of a Piezo channel, suggesting that Piezo1 gating does not exclusively depend on changes in mechanical force. This is important, since it raises the possibility that endogenous agonists of Piezo1 exist which may play an important role in modulating mechanotransduction. Secondly, Yoda1 will provide a valuable tool to facilitate studies aimed at elucidating Piezo1 gating mechanism and exploring its functional significance in various biological processes (see for instance accompanying paper).

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Author details

1. Ruhma Syeda

   1. Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, United States
   2. University of California, San Diego, La Jolla, United States

   Contribution

   RS, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

2. Jie Xu

   Genomics Institute of the Novartis Research Foundation, San Diego, United States

   Contribution

   JX, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

3. Adrienne E Dubin

   Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, United States

   Contribution

   AED, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

4. Bertrand Coste

   Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, United States

   Present address

   Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Centre national de la recherche scientifique, Aix Marseille Université, La Jolla, United States

   Contribution

   BC, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

5. Jayanti Mathur

   Genomics Institute of the Novartis Research Foundation, San Diego, United States

   Contribution

   JM, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

6. Truc Huynh

   Genomics Institute of the Novartis Research Foundation, San Diego, United States

   Contribution

   TH, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

7. Jason Matzen

   Genomics Institute of the Novartis Research Foundation, San Diego, United States

   Contribution

   JM, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

8. Jianmin Lao

   Genomics Institute of the Novartis Research Foundation, San Diego, United States

   Contribution

   JL, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

9. David C Tully

   Genomics Institute of the Novartis Research Foundation, San Diego, United States

   Present address

   Novartis Institutes for Biomedical Research, Emeryville, United States

   Contribution

   DCT, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

10. Ingo H Engels

    Genomics Institute of the Novartis Research Foundation, San Diego, United States

    Present address

    Department of Pharmaceutical Sciences, Appalachian College of Pharmacy, Oakwood, United States

    Contribution

    IHE, Conception and design, Analysis and interpretation of data

    Competing interests

    The authors declare that no competing interests exist.

11. H Michael Petrassi

    Genomics Institute of the Novartis Research Foundation, San Diego, United States

    Contribution

    HMP, Conception and design, Analysis and interpretation of data

    Competing interests

    The authors declare that no competing interests exist.

12. Andrew M Schumacher

    Genomics Institute of the Novartis Research Foundation, San Diego, United States

    Contribution

    AMS, Conception and design, Analysis and interpretation of data

    Competing interests

    The authors declare that no competing interests exist.

13. Mauricio Montal

    University of California, San Diego, La Jolla, United States

    Contribution

    MM, Conception and design, Analysis and interpretation of data

    Competing interests

    The authors declare that no competing interests exist.

14. Michael Bandell

    Genomics Institute of the Novartis Research Foundation, San Diego, United States

    Contribution

    MB, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

    For correspondence

    mbandell@gnf.org

    Competing interests

    The authors declare that no competing interests exist.

15. Ardem Patapoutian

    Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, United States

    Contribution

    AP, Conception and design, Analysis and interpretation of data, Drafting or revising the article

    For correspondence

    ardem@scripps.edu

    Competing interests

    The authors declare that no competing interests exist.

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