Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology

doi:10.1016/j.pbiomolbio.2017.07.011

Progress in Biophysics and Molecular Biology

Volume 130, Part B, November 2017, Pages 244-253

https://doi.org/10.1016/j.pbiomolbio.2017.07.011 Get rights and content

Abstract

Discovery of Piezo channels and the reporting of their sensitivity to the inhibitor GsMTx4 were important milestones in the study of non-selective cationic mechanosensitive channels (MSCs) in normal physiology and pathogenesis. GsMTx4 had been used for years to investigate the functional role of cationic MSCs, especially in muscle tissue, but with little understanding of its target or inhibitory mechanism. The sensitivity of Piezo channels to bilayer stress and its robust mechanosensitivity when expressed in heterologous systems were keys to determining GsMTx4's mechanism of action. However, questions remain regarding Piezo's role in muscle function due to the non-selective nature of GsMTx4 inhibition toward membrane mechanoenzymes and the implication of MCS channel types by genetic knockdown. Evidence supporting Piezo like activity, at least in the developmental stages of muscle, is presented. While the MSC targets of GsMTx4 in muscle pathology are unclear, its muscle protective effects are clearly demonstrated in two recent in situ studies on normal cardiomyocytes and dystrophic skeletal muscle. The muscle protective function may be due to the combined effect of GsMTx4's inhibitory action on cationic MSCs like Piezo and TRP, and its potentiation of repolarizing K⁺ selective MSCs like K2P and SAKCa. Paradoxically, the potent in vitro action of GsMTx4 on many physiological functions seems to conflict with its lack of in situ side-effects on normal animal physiology. Future investigations into cytoskeletal control of sarcolemma mechanics and the suspected inclusion of MSCs in membrane micro/nano sized domains with distinct mechanical properties will aide our understanding of this dichotomy.

Section snippets

The historical conundrum of mechanosensitive channels

Mechanosensitive currents were first recorded over 35 years ago in vertebrate outer hair cells, the primary auditory mechanoreceptors (Corey and Hudspeth, 1979). This was followed soon after by recordings of single mechanosensitive ion channels (MSCs) when negative pressure was applied to cell-attached patches from skeletal muscle (Guharay and Sachs, 1984). Because the patch produces a targeted stress stimulus and high resolution channel recordings, it became the primary assay used in the early

MSC gating mechanisms and molecular identity

MSCs fall into two general physiological roles depending on their ion selectivity; inhibitory hyperpolarizing (K⁺ selective) and the excitatory depolarizing (non-selective cationic). They can be further categorized by their mechanosensory mechanisms. The force to open MSCs can be transmitted via ECM/cytoskeletal tethers to the channel or directly through bilayer tension and curvature changes near the channel. Channels gated through their association with the ECM/cytoskeleton are difficult to

Piezo – the missing link

In 2010 a ubiquitously expressed family of channels was identified called Piezo, that was cation selective and displayed rapid voltage dependent inactivation in patches and whole-cell mechanical assays (Coste et al., 2010). Like K2P channels, Piezo has recently been reconstituted in different lipid based assays devoid of cytoskeletal intervention and shown to be directly gated by lipid tension (Syeda et al., 2016, Cox et al., 2016). However channel gating is definitely modulated by cytoskeleton

GsMTx4 mechanism of inhibition and modulation of piezo vs K⁺ selective MSCs

In 2000 a peptide inhibitor of the inactivating non-selective cation MSCs was discovered (Suchyna et al., 2000), called Grammostola Mechanotoxin #4 (GsMTx4), and became an important identifier and tool for investigating the physiological role of these channels (Bowman et al., 2007). The peptide was isolated by screening spider venoms against an endogenously expressed cation selective MSCs from rat astrocytes. GsMTx4 appeared to inhibit multiple types of endogenous cation selective MSCs in

Does piezo contribute to endogenous cationic MS currents in normal muscle physiology and pathology?

While Piezo 1 and 2 were shown to have low expression levels in adult mouse skeletal and cardiac muscle (Coste et al., 2010), we have observed the Piezo1 sequence is present in a cDNA library constructed from C2C12 mouse myoblast mRNA (Dr. Philip Gottlieb, person communication). In differentiated myofibers, Piezo channels may have low expression levels on the sarcolemma unless triggered to translocate from cytoplasmic pools during pathogenesis. Precedence for the translocation of channels to

Therapeutic potential of GsMTx4

Impaired cation/Ca²⁺ homeostasis due to elevated sarcolemma cation flux, observed in disease states such as Duchene muscular dystrophy and cardiac ischemia (Miyamae et al., 1996) and hypertrophy (Clemo et al., 1998), is a hallmark of muscle pathology. Significant contributors to the cation imbalance are the non-selective cationic MSCs among which TRP channel dysregulation has frequently been invoked (Iwata et al., 2013, Gailly, 2012). GsMTx4 has been used to implicate multiple TRP channels in

MSCs in normal physiology versus pathology

As GsMTx4 has become an important tool for elucidating the role of cationic MSCs in normal physiology and pathologenesis, an interesting dichotomy has arisen. GsMTx4 has revealed that MSCs “apparently” contribute significantly to normal short-term and developmental physiology (examples: arterial pressure regulation (Spassova et al., 2006, Fanchaouy et al., 2007, Gilbert et al., 2014, Gonzales et al., 2014), skeletal muscle pressor reflex (Copp et al., 2016), cardiac stretch induced slow force

Conclusions

Piezo channels have filled a significant gap in our knowledge of the molecular identities of MSCs. The lability of its distinctive voltage dependent inactivation property is a critical area of study as its disruption has been tied to multiple disease states. While it has not been shown to be highly expressed in muscle cells, we presented evidence that channels with the hallmark properties of Piezo may contribute a significant component of the MSC current in differentiating myotubes. As aberrant

Competing interests

GsMTx4 is licensed to Tonus Therapeutics. Thomas Suchyna has part ownership in this company.

Disclaimer

GsMTx4, in both the L and D forms, have been tested on multiple normal and disease models as discussed in section labeled MSCs in Normal Physiology versus Pathology, and has been shown to affect multiple normal physiological processes in vitro. GsMTx4 is a membrane tension modifier and therefore may target multiple sarcolemma mechanoenzymes. These efficacy tests were short-term treatments and do not address the issues of long-term toxicity. Long term toxicity tests are currently being planned

Acknowledgements

This work was funded by a DoD grant project No. DM102091 and a NIH grant HL054887 awarded to Dr. Frederick Sachs.

References (130)

C. Bae et al.
Human PIEZO1: removing inactivation
Biophys. J.
(2013)
C.L. Bowman
Mechanosensitive ion channels and the peptide inhibitor GsMTx-4: history, properties, mechanisms and pharmacology
Toxicon
(2007)
G.T. Charras
Life and times of a cellular bleb
Biophys. J.
(2008)
V. Dyachenko
Mechanical deformation of ventricular myocytes modulates both TRPC6 and Kir2.3 channels
Cell Calcium
(2009)
M. Fanchaouy
Stretch-elicited calcium responses in the intact mouse thoracic aorta
Cell Calcium
(2007)
A. Franco et al.
Open channel block by gadolinium ion of the stretch-inactivated ion channel in mdx myotubes
Biophysical J.
(1991)
O. Friedrich
Microarchitecture is severely compromised but motor protein function is preserved in dystrophic mdx skeletal muscle
Biophys. J.
(2010)
O. Friedrich
Mechano-regulation of the beating heart at the cellular level–mechanosensitive channels in normal and diseased heart
Prog. Biophys. Mol. Biol.
(2012)
P. Gailly
TRP channels in normal and dystrophic skeletal muscle
Curr. Opin. Pharmacol.
(2012)
R. Gnanasambandam
GsMTx4: mechanism of inhibiting mechanosensitive ion channels
Biophysical J.
(2017)

C.X. Gu et al.

Stretch-activation and stretch-inactivation of Shaker-IR, a voltage- gated K+ channel

Biophys. J.

(2001)

I. Hanukoglu et al.

Epithelial sodium channel (ENaC) family: phylogeny, structure–function, tissue distribution, and associated inherited diseases

Gene

(2016)

R. Inoue et al.

Mechanosensitive TRP channels in cardiovascular pathophysiology

Pharmacol. Ther.

(2009)

H.J. Jung

Lipid membrane interaction and antimicrobial activity of GsMTx-4, an inhibitor of mechanosensitive channel

Biochem. Biophys. Res. Commun.

(2006)

K. Kurima

TMC1 and TMC2 localize at the site of mechanotransduction in mammalian inner ear hair cell stereocilia

Cell Rep.

(2015)

C. Liu et al.

Forcing open TRP channels: mechanical gating as a unifying activation mechanism

Biochem. Biophys. Res. Commun.

(2015)

F. Maingret

TRAAK is a mammalian neuronal mechano-gated K + channel

J. Biol. Chem.

(1999)

D.W. McBride et al.

Pressure-clamp technique for measurement of the relaxation kinetics of mechanosensitive channels

Trends Neurosci.

(1993)

K. Nishizawa

Effects of Lys to Glu mutations in GsMTx4 on membrane binding, peptide orientation, and self-association propensity, as analyzed by molecular dynamics simulations

Biochim. Biophys. Acta (BBA)-Biomembranes

(2015)

L.W. Ostrow et al.

Stretch induced endothelin-1 secretion by adult rat astrocytes involves calcium influx via stretch-activated ion channels (SACs)

Biochem. Biophys. Res. Commun.

(2011)

S.P. Park

A tarantula spider toxin, GsMTx4, reduces mechanical and neuropathic pain

Pain

(2008)

H.M. Piper et al.

Prime causes of rapid cardiomyocyte death during reperfusion

Ann. Thorac. Surg.

(1999)

Y.O. Posokhov

Is lipid bilayer binding a common property of inhibitor cysteine knot ion-channel blockers?

Biophys. J.

(2007)

K. Retailleau

Piezo1 in smooth muscle cells is involved in hypertension-dependent arterial remodeling

Cell Rep.

(2015)

E.A. Rog-Zielinska

The living scar–cardiac fibroblasts and the injured heart

Trends Mol. Med.

(2016)

N.W. Schmidt et al.

Antimicrobial peptides and induced membrane curvature: geometry, coordination chemistry, and molecular engineering

Curr. Opin. Solid State Mater. Sci.

(2013)

N. Alessandri-Haber

TRPC1 and TRPC6 channels cooperate with TRPV4 to mediate mechanical hyperalgesia and nociceptor sensitization

J. Neurosci.

(2009)

J. Árnadóttir et al.

Eukaryotic mechanosensitive channels

Annu. Rev. Biophys.

(2010)

C. Bae et al.

The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4

Biochemistry

(2011)

C. Bae

Xerocytosis is caused by mutations that alter the kinetics of the mechanosensitive channel PIEZO1

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

(2013)

S.R. Besch et al.

High-speed pressure clamp

Pflugers Archiv-European J. Physiol.

(2002)

M. Beurg et al.

Conductance and block of hair-cell mechanotransducer channels in transmembrane channel–like protein mutants

J. General Physiol.

(2014)

M. Biro

Cell cortex composition and homeostasis resolved by integrating proteomics and quantitative imaging

Cytoskeleton

(2013)

S.G. Brohawn et al.

Crystal structure of the human K2P TRAAK, a lipid-and mechano-sensitive K+ ion channel

Science

(2012)

S.G. Brohawn et al.

Physical mechanism for gating and mechanosensitivity of the human TRAAK K+ channel

Nature

(2014)

J. Chemin

Mechanisms underlying excitatory effects of group I metabotropic glutamate receptors via inhibition of 2P domain K+ channels

EMBO J.

(2003)

J. Chemin

A phospholipid sensor controls mechanogating of the K+ channel TREK-1

EMBO J.

(2005)

A.P. Christensen et al.

TRP channels in mechanosensation: direct or indirect activation?

Nat. Rev. Neurosci.

(2007)

H.F. Clemo et al.

Persistent activation of a swelling-activated cation current in ventricular myocytes from dogs with tachycardia-induced congestive heart failure

Circ. Res.

(1998)

W.D. Coley

Effect of genetic background on the dystrophic phenotype in mdx mice

Hum. Mol. Genet.

(2015)

S.W. Copp

The mechano-gated channel inhibitor GsMTx4 reduces the exercise pressor reflex in decerebrate rats

J. Physiol.

(2016)

D.P. Corey et al.

Ionic basis of the receptor potential in a vertebrate hair cell

Nature

(1979)

B. Coste

Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels

Science

(2010)

B. Coste

Piezo proteins are pore-forming subunits of mechanically activated channels

Nature

(2012)

B. Coste

Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis

Proc. Natl. Acad. Sci.

(2013)

C.D. Cox

Removal of the mechanoprotective influence of the cytoskeleton reveals PIEZO1 is gated by bilayer tension

Nat. Commun.

(2016)

A.L. Eastwood et al.

Insight into DEG/ENaC channel gating from genetics and structure

Physiology

(2012)

G.G. Ernstrom et al.

Genetics of sensory mechanotransduction

Annu. Rev. Genet.

(2002)

M. Fink

Cloning, functional expression and brain localization of a novel unconventional outward rectifier K+ channel

EMBO J.

(1996)

A. Franco et al.

Calcium entry through stretch-inactivated ion channels in mdx myotubes

Nature

(1990)

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The mechanosensitive ion channel, Piezo1, is responsible for transducing mechanical stimuli into intracellular biochemical signals and has been identified within periodontal ligament cells (PDLCs). Nonetheless, the precise biologic function of Piezo1 in the regulation of alveolar bone remodeling by PDLCs during compressive forces remains unclear. Therefore, this study focused on elucidating the role of the Piezo1 channel in alveolar bone remodeling and uncovering its underlying mechanisms.
PDLCs were subjected to compressive force and Piezo1 inhibitors. Piezo1 and β-catenin expressions were quantified by quantitative reverse transcription polymerase chain reaction and Western blot. The intracellular calcium concentration was measured using Fluo-8 AM staining. The osteogenic and osteoclastic activities were assessed using alkaline phosphatase staining, enzyme-linked immunosorbent assay, quantitative reverse transcription polymerase chain reaction, and Western blot. In vivo, orthodontic tooth movement was used to determine the effects of Piezo1 on alveolar bone remodeling.
Piezo1 and activated β-catenin expressions were upregulated under compressive force. Piezo1 inhibition reduced β-catenin activation, osteogenic differentiation, and osteoclastic activities. β-catenin knockdown reversed the increased osteogenic differentiation but had little impact on osteoclastic activities. In vivo, Piezo1 inhibition led to decreased tooth movement distance, accompanied by reduced β-catenin activation and expression of osteogenic and osteoclastic markers on the compression side.
The Piezo1 channel is a key mechanotransduction component of PDLCs that senses compressive force and activates β-catenin to regulate alveolar bone remodeling.
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Osteoarthritis (OA) is a prevalent disease among elderly people and is often characterized by chronic joint pain and dysfunction. Recently, growing evidence of chondrocyte senescence in the pathogenesis of OA has been found, and targeting senescence has started to be recognized as a therapeutic approach for OA. Piezo1, a mechanosensitive Ca²⁺ channel, has been reported to be harmful in sensing abnormal mechanical overloading and leading to chondrocyte apoptosis. However, whether Piezo1 can transform mechanical signals into senescence signals has rarely been reported. In this study, we found that severe OA cartilage expressed more Piezo1 and the senescence markers p16 and p21. 24 h of periodic mechanical stress induced chondrocyte senescence in vitro. In addition, we demonstrated the pivotal role of Piezo1 in OA chondrocyte senescence induced by mechanical stress. Piezo1 sensed mechanical stress and promoted chondrocyte senescence via its Ca²⁺ channel ability. Moreover, Piezo1 promoted SASP factors production under mechanical stress, particularly in IL-6 and IL-1β. p38MAPK and NF-κB activation were two key pathways that responded to Piezo1 activation and promoted IL-6 and IL-1β production, respectively. Collectively, our study revealed a connection between abnormal mechanical stress and chondrocyte senescence, which was mediated by Piezo1.
Two types of peptides derived from the neurotoxin GsMTx4 inhibit a mechanosensitive potassium channel by modifying the mechanogate
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Atrial fibrillation is the most common sustained cardiac arrhythmia in humans. Current atrial fibrillation antiarrhythmic drugs have limited efficacy and carry the risk of ventricular proarrhythmia. GsMTx4, a mechanosensitive channel–selective inhibitor, has been shown to suppress arrhythmias through the inhibition of stretch-activated channels (SACs) in the heart. The cost of synthesizing this peptide is a major obstacle to clinical use. Here, we studied two types of short peptides derived from GsMTx4 for their effects on a stretch-activated big potassium channel (SAKcaC) from the heart. Type I, a 17-residue peptide (referred to as Pept 01), showed comparable efficacy, whereas type II (i.e., Pept 02), a 10-residue peptide, exerted even more potent inhibitory efficacy on SAKcaC compared with GsMTx4. We identified through mutagenesis important sequences required for peptide functions. In addition, molecular dynamics simulations revealed common structural features with a hydrophobic head followed by a positively charged protrusion that may be involved in peptide channel–lipid interactions. Furthermore, we suggest that these short peptides may inhibit SAKcaC through a specific modification to the mechanogate, as the inhibitory effects for both types of peptides were mostly abolished when tested with a mechano-insensitive channel variant (STREX-del) and a nonmechanosensitive big potassium (mouse Slo1) channel. These findings may offer an opportunity for the development of a new class of drugs in the treatment of cardiac arrhythmia generated by excitatory SACs in the heart.
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Citation Excerpt :
GsMTx-4 also strongly inhibited Ca2+ store release and consequently α- and δ-granule release after U46619 activation (Vemana, Karim, Conlon, & Khasawneh, 2015). GsMTx-4 also impairs TRPC1 and mechanosensitive Piezo channel functions, indicating a combined inhibitory effect of this drug in platelets (Liu et al., 2021; Spassova, Hewavitharana, Xu, Soboloff, & Gill, 2006; Suchyna, 2017). Incubation of platelets with a TRPC6 specific antibody recognizing amino acid residues 573–586 in the second extracellular loop domain, inhibited thrombin-induced δ-granule release, suggesting a key role of TRPC6-mediated Ca2+ entry in platelet degranulation (Lopez et al., 2015).
Transient receptor potential (TRP) proteins form a superfamily of cation channels that are expressed in a wide range of tissues and cell types. During the last years, great progress has been made in understanding the molecular complexity and the functions of TRP channels in diverse cellular processes, including cell proliferation, migration, adhesion and activation. The diversity of functions depends on multiple regulatory mechanisms by which TRP channels regulate Ca²⁺ entry mechanisms and intracellular Ca²⁺ dynamics, either through membrane depolarization involving cation influx or store- and receptor-operated mechanisms. Abnormal function or expression of TRP channels results in vascular pathologies, including hypertension, ischemic stroke and inflammatory disorders through effects on vascular cells, including the components of blood vessels and platelets. Moreover, some TRP family members also regulate megakaryopoiesis and platelet production, indicating a complex role of TRP channels in pathophysiological conditions. In this review, we describe potential roles of TRP channels in megakaryocytes and platelets, as well as their contribution to diseases such as thrombocytopenia, thrombosis and stroke. We also critically discuss the potential of TRP channels as possible targets for disease prevention and treatment.
Foodborne compounds that alter plasma membrane architecture can modify the response of intestinal cells to shear stress in vitro
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In order to investigate the molecular events potentially connecting cholesterol homeostasis and biomechanical compliance, we investigated if the treatments could modulate the expression/localization of proteins essential for cell structure and mechanosensory apparatus. This includes mechano-gated ion channels PIEZO1 (Coste et al., 2010; Suchyna, 2017), caveolin-1 which organizes cholesterol rich mechanosenstive membrane domains (Moreno-Vicente et al., 2018; Hubert et al., 2020) and the actin cytoskeleton, which provides essential support in the intracellular compartment from the nucleus to the surface. Incubation of HT-29 cells with AOH resulted in a concentration dependent increase of the PIEZO1 channels signal.
In order to ensure barrier function, intestinal cells need to respond promptly to biomechanical stimulation and to adapt constantly to physical cues. To this aim, cell membranes are essential and rely extensively on lipid metabolism and turnover. These can be tuned via nutrition, pharmacological treatment, or exposure to xenobiotics, however, knowledge on the impact of lifestyle and diet on intestinal cells' biomechanical compliance is relatively limited. Building on this, two intestinal cell models (non-transformed human colon epithelial cells HCEC-1CT and the colon adenocarcinoma cell line HT-29) were systematically compared in terms of cholesterol content, membrane fluidity, actin cytoskeletal organization, expression of mechano-gated PIEZO1 channels and caveolin-1. Biomechanical compliance was evaluated with the application of fluid shear stress (force response 0.75–1.5 dyn/cm²). As model substances the food contaminant mycotoxin alternariol (AOH, 0.01–10 μM) was chosen in virtue of its putative structural analogy with cholesterol. AOH was compared to the cholesterol lowering agent lovastatin (LOVA, 0.01–10 μM) and to water-soluble cholesterol (MβCD-CHOL, 0.01–10 μg/ml). Exposure to AOH, LOVA and MβCD-CHOL coherently modulated membrane cholesterol, expression of PIEZO1 and caveolin-1 as well as the formation of actin stress fibers. These effects were functionally relevant since they modified the force response profile to fluid shear stress (morphological adaption and [Ca²⁺]_i). In sum, we could demonstrate a novel role for exogenous or endogenous molecules in shaping intestinal mechanotransduction via regulation of cholesterol homeostasis and plasma membrane architecture.
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Published by Elsevier Ltd.

Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology

Abstract

Section snippets

The historical conundrum of mechanosensitive channels

MSC gating mechanisms and molecular identity

Piezo – the missing link

GsMTx4 mechanism of inhibition and modulation of piezo vs K+ selective MSCs

Does piezo contribute to endogenous cationic MS currents in normal muscle physiology and pathology?

Therapeutic potential of GsMTx4

MSCs in normal physiology versus pathology

Conclusions

Competing interests

Disclaimer

Acknowledgements

Biophys. J.

Toxicon

Biophys. J.

Cell Calcium

Cell Calcium

Biophysical J.

Biophys. J.

Prog. Biophys. Mol. Biol.

Curr. Opin. Pharmacol.

Biophysical J.

Biophys. J.

Gene

Pharmacol. Ther.

Biochem. Biophys. Res. Commun.

Cell Rep.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Trends Neurosci.

Biochim. Biophys. Acta (BBA)-Biomembranes

Biochem. Biophys. Res. Commun.

Pain

Ann. Thorac. Surg.

Biophys. J.

Cell Rep.

Trends Mol. Med.

Curr. Opin. Solid State Mater. Sci.

TRPC1 and TRPC6 channels cooperate with TRPV4 to mediate mechanical hyperalgesia and nociceptor sensitization

J. Neurosci.

Eukaryotic mechanosensitive channels

Annu. Rev. Biophys.

The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4

Biochemistry

Xerocytosis is caused by mutations that alter the kinetics of the mechanosensitive channel PIEZO1

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

High-speed pressure clamp

Pflugers Archiv-European J. Physiol.

Conductance and block of hair-cell mechanotransducer channels in transmembrane channel–like protein mutants

J. General Physiol.

Cell cortex composition and homeostasis resolved by integrating proteomics and quantitative imaging

Cytoskeleton

Crystal structure of the human K2P TRAAK, a lipid-and mechano-sensitive K+ ion channel

Science

Physical mechanism for gating and mechanosensitivity of the human TRAAK K+ channel

Nature

Mechanisms underlying excitatory effects of group I metabotropic glutamate receptors via inhibition of 2P domain K+ channels

EMBO J.

A phospholipid sensor controls mechanogating of the K+ channel TREK-1

EMBO J.

TRP channels in mechanosensation: direct or indirect activation?

Nat. Rev. Neurosci.

Persistent activation of a swelling-activated cation current in ventricular myocytes from dogs with tachycardia-induced congestive heart failure

Circ. Res.

Effect of genetic background on the dystrophic phenotype in mdx mice

Hum. Mol. Genet.

The mechano-gated channel inhibitor GsMTx4 reduces the exercise pressor reflex in decerebrate rats

J. Physiol.

Ionic basis of the receptor potential in a vertebrate hair cell

Nature

Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels

Science

Piezo proteins are pore-forming subunits of mechanically activated channels

Nature

Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis

Proc. Natl. Acad. Sci.

Removal of the mechanoprotective influence of the cytoskeleton reveals PIEZO1 is gated by bilayer tension

Nat. Commun.

GsMTx4 mechanism of inhibition and modulation of piezo vs K⁺ selective MSCs