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Catalog No.: GC38465

GsMTx4 selectively inhibits cation-permeable mechanosensitive channels (MSCs) belonging to the Piezo and TRP channel families.

GsMTx4 Chemical Structure

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Cell experiment [1]:

Cell lines

HEK 293 cells

Preparation method

For Piezo1 channels, the extracellular solution contained 145 mM NaCl, 5 mM KCl, 3 mM MgCl2, 0.1 mM CaCl2, and 10 mM HEPES (pH 7.4). The pipette solution contained 133 mM CsCl, 10 mM HEPES (pH 7.4). The inhibition produced by application of GsMTx4 was followed by ∼60 s of washout, followed by application of WT GsMTx4 as a control.

Reaction Conditions

5 μM GsMTx4, 40s


GsMTx4 is a spider venom peptide that inhibits cationic mechanosensitive channels (MSCs). A model placing GsMTx4 at the membrane surface, where it is stabilized by the lysines, and occupying a small fraction of the surface area in unstressed membranes. When applied tension reduces lateral pressure in the lipids, the peptides penetrate deeper acting as “area reservoirs” leading to partial relaxation of the outer monolayer, thereby reducing the effective magnitude of stimulus acting on the MSC gate.

Animal experiment [2]:

Animal models

Male C57BL/6 mice

Dosage form

To the WT and ClockΔ19/Δ19 mice, GsMTx4 or vehicle was administered via intraperitoneal injection (IP) at two different time-points, Z12- and ZT0-IP (higher and lower Piezo1 expression periods in the WT mice, respectively). The WT and ClockΔ19/Δ19 mice were injected with 0.75 (low dose-IP) or 1.5 mg/kg (high dose-IP) of GsMTx4 in 100 μL of distilled water.


VF decreased at ZT12-IP in WT mice only with high dose of GsMTx4 but showed no effects in ClockΔ19/Δ19 mice. GsMTx4 did not affect Uvol in both mice at ZT12-IP. A decrease in Uvol was observed in both mice at ZT0-IP; however, it was unrelated to GsMTx4-IP. The effects of GsMTx4 changed associated with the circadian clock and Piezo1 expression level.


[1]. Gnanasambandam R, et al. GsMTx4: Mechanism of Inhibiting Mechanosensitive Ion Channels. Biophys J. 2017 Jan 10;112(1):31-45.

[2]. Ihara, Tatsuya, et al. "Different effects of GsMTx4 on nocturia associated with the circadian clock and Piezo1 expression in mice." Life Sciences 278 (2021): 119555.


GsMTx4 is a 34 amino acid spider venom peptide and belongs to the huwentoxin-1 family[1]. GsMTx4 selectively inhibits cation-permeable mechanosensitive channels (MSCs) belonging to the Piezo, TRPC1 and TRPC6 channels.

GsMTx4 is similar to many other channel-active peptides isolated from spider venom, which are small (3–5 kD) amphipathic molecules built on a conserved inhibitory cysteine-knot (ICK) backbone[4].GsMTx4 has high potency for inhibiting mechanosensitive channels, and its inhibition is not stereospecific, i.e., both its enantiomers (L- and D-form) inhibiting MSCs[3].

GsMTx4 significantly attenuates bladder hyperactivity[2]. Intraperitoneal injection of GsMTx-4 has been shown to reduce mechanical hyperalgesia induced by carrageenan or sciatic nerve injury[5], although it does not inhibit SAC currents in cultured DRG neurons[6].

GsMTx4 is an important pharmacological tool for identifying the role of these excitatory MSCs in normal physiology and pathology[4].

[1]. Suchyna TM, et al. Identification of a peptide toxin from Grammostola spatulata spider venom that blocks cation-selective stretch-activated channels. J Gen Physiol. 2000 May;115(5):583-98.
[2]. Liu Q, et al. Increased Piezo1 channel activity in interstitial Cajal-like cells induces bladder hyperactivity by functionally interacting with NCX1 in rats with cyclophosphamide-induced cystitis. Exp Mol Med. 2018 May 7;50(5):60.
[3]. Suchyna T.M., Tape S.E., Gottlieb P.A. Bilayer-dependent inhibition of mechanosensitive channels by neuroactive peptide enantiomers. Nature. 2004;430:235–240.
[4]. Gnanasambandam R, et al. GsMTx4: Mechanism of Inhibiting Mechanosensitive Ion Channels. Biophys J. 2017 Jan 10;112(1):31-45.
[5]. Park SP, et al. A tarantula spider toxin, GsMTx4, reduces mechanical and neuropathic pain. Pain. 2008;137:208–217.
[6]. Drew LJ, , et al.. High-threshold mechanosensitive ion channels blocked by a novel conopeptide mediate pressure-evoked pain. PLoS ONE. 2007;2:e515.

Chemical Properties

Cas No. 1209500-46-8 SDF
Chemical Name Gly-Cys-Leu-Glu-Phe-Trp-Trp-Lys-Cys-Asn-Pro-Asn-Asp-Asp-Lys-Cys-Cys-Arg-Pro-Lys-Leu-Lys-Cys-Ser-Lys-Leu-Phe-Lys-Leu-Cys-Asn-Phe-Ser-Phe
Formula C185H279N49O45S6 M.Wt 4101.89
Solubility Water : 16.67 mg/mL Storage Store at -20°C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

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Research Update

The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4

Biochemistry 2011 Jul 26;50(29):6295-300.PMID:21696149DOI:10.1021/bi200770q.

Cells can respond to mechanical stress by gating mechanosensitive ion channels (MSCs). The cloning of Piezo1, a eukaryotic cation selective MSC, defines a new system for studying mechanical transduction at the cellular level. Because Piezo1 has electrophysiological properties similar to those of endogenous cationic MSCs that are selectively inhibited by the peptide GsMTx4, we tested whether the peptide targets Piezo1 activity. Extracellular GsMTx4 at micromolar concentrations reversibly inhibited ∼80% of the mechanically induced current of outside-out patches from transfected HEK293 cells. The inhibition was voltage insensitive, and as seen with endogenous MSCs, the mirror image d enantiomer inhibited like the l. The rate constants for binding and unbinding based on Piezo1 current kinetics provided association and dissociation rates of 7.0 × 10(5) M(-1) s(-1) and 0.11 s(-1), respectively, and a K(D) of ∼155 nM, similar to values previously reported for endogenous MSCs. Consistent with predicted gating modifier behavior, GsMTx4 produced an ∼30 mmHg rightward shift in the pressure-gating curve and was active on closed channels. In contrast, streptomycin, a nonspecific inhibitor of cationic MSCs, showed the use-dependent inhibition characteristic of open channel block. The peptide did not block currents of the mechanical channel TREK-1 on outside-out patches. Whole-cell Piezo1 currents were also reversibly inhibited by GsMTx4, and although the off rate was nearly identical to that of outside-out patches, differences were observed for the on rate. The ability of GsMTx4 to target the mechanosensitivity of Piezo1 supports the use of this channel in high-throughput screens for pharmacological agents and diagnostic assays.

Mechanosensitive Piezo1 channels mediate renal fibrosis

JCI Insight 2022 Apr 8;7(7):e152330.PMID:35230979DOI:10.1172/jci.insight.152330.

Kidney fibrosis is the final common pathway of progressive kidney diseases, the underlying mechanisms of which are not fully understood. The purpose of the current study is to investigate a role of Piezo1, a mechanosensitive nonselective cation channel, in kidney fibrosis. In human fibrotic kidneys, Piezo1 protein expression was markedly upregulated. The abundance of Piezo1 protein in kidneys of mice with unilateral ureter obstruction (UUO) or with folic acid treatment was significantly increased. Inhibition of Piezo1 with nonspecific inhibitor GsMTx4 markedly ameliorated UUO- or folic acid-induced kidney fibrosis. Mechanical stretch, compression, or stiffness induced Piezo1 activation and profibrotic responses in human HK2 cells and primary cultured mouse proximal tubular cells (mPTCs), which were greatly prevented by inhibition or silence of Piezo1. TGF-β1 induced increased Piezo1 expression and profibrotic phenotypic alterations in HK2 cells and mPTCs, which were again markedly prevented by inhibition of Piezo1. Activation of Piezo1 by Yoda1, a Piezo1 agonist, caused calcium influx and profibrotic responses in HK2 cells and induced calcium-dependent protease calpain2 activation, followed by adhesion complex protein talin1 cleavage and upregulation of integrin β1. Also, Yoda1 promoted the link between ECM and integrin β1. In conclusion, Piezo1 is involved in the progression of kidney fibrosis and profibrotic alterations in renal proximal tubular cells, likely through activating calcium/calpain2/integrin β1 pathway.

GsMTx4-D provides protection to the D2.mdx mouse

Neuromuscul Disord 2018 Oct;28(10):868-877.PMID:30174173DOI:10.1016/j.nmd.2018.07.005.

Duchenne muscular dystrophy is a life-limiting muscle disease that has no current effective therapy. Despite mounting evidence that dysregulation of mechanosensitive ion channels is a significant contributor to dystrophy pathogenesis, effective pharmacologic strategies targeting these channels are lacking. GsMTx4, and its enantiomer GsMTx4-D, are peptide inhibitors of mechanosensitive channels with identical activity. In previous studies, acute in vitro application of GsMTx4 to dystrophic murine muscle effectively reduced the excess MSC dependent calcium influx linked to contraction-induced muscle damage. Here we sought to determine if in vivo treatment with GsMTx4-D proffered benefit in the D2.mdx mouse. GsMTx4-D showed a 1-week half-life when administered by subcutaneous injection over four weeks. Informed by these results, D2.mdx mice were then treated by a subcutaneous injection regimen of GsMTx4-D for six weeks followed by determination of muscle mass, muscle susceptibility to eccentric contraction injury and multiple histological indicators of disease progression. The mice showed a reduction in the loss of muscle mass and a decrease in susceptibility to contraction induced injury. These protective effects were realized without reduction in fibrosis, supporting a model where GsMTx4-D acts directly on muscle cells. We propose GsMTx4-D represents a promising new therapy to slow disease progression and may complement other therapies such as anti-inflammatory agents and gene-replacement strategies.

GsMTx4-D is a cardioprotectant against myocardial infarction during ischemia and reperfusion

J Mol Cell Cardiol 2016 Sep;98:83-94.PMID:27423272DOI:10.1016/j.yjmcc.2016.07.005.

GsMTx4 is a selective inhibitor of cationic mechanosensitive ion channels (MSCs) and has helped establish the role of MSCs in cardiac physiology. Inhomogeneous local mechanical stresses due to hypercontracture and swelling during ischemic reperfusion injury (IRI) likely induce elevated MSC activity that can contribute to cation imbalance. The aim of this study was to determine if the D enantiomer of GsMTx4 can act as a cardioprotectant in a mouse IRI model. Ischemia and reperfusion involved ligating a coronary artery followed by release of the ligature. GsMTx4-D was tested by either acute intravenous injection during the ischemic event or by two day pretreatment by intraperitoneal injection, both methods achieving similar results. Based on pharmacokinetic studies, GsMTx4-D dosage was set to achieve expected plasma concentrations between 50 and 5000nM and heart tissue concentrations between 1 and 200nM by intravenous injection. Relative to vehicle injected animals, GsMTx4-D reduced infarct area by ~40% for acute and pretreated animals for both 20 and 45min ischemic challenges. Many indicators of cardiac output were indistinguishable from sham-treated control hearts after GsMTx4-D treatment showing improvement at both 4 and 48h post ischemia, and premature ventricular beats immediately following reperfusion were also significantly reduced. To determine if GsMTx4-D cardioprotection could act directly at the level of cardiomyocytes, we tested its effects in vitro on indicators of IRI damage like cation influx and activation of inflammatory kinases in isolated myocytes cultured under hypoxic conditions. Hypoxia challenged cardiomyocytes treated with 10μM GsMTx4-D showed improved contractility and near normal contraction-related Ca(2+) influx. GsMTx4-D inhibited indicators of ischemic damage such as the apoptotic signaling system JNK/c-Jun, but also inhibited the energy response signaling system Akt kinase. We conclude that GsMTx4-D is a potent cardioprotectant in vivo that may act directly on cardiomyocytes and potentially be useful in multidrug strategies to treat IRI.

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

Prog Biophys Mol Biol 2017 Nov;130(Pt B):244-253.PMID:28778608DOI:10.1016/j.pbiomolbio.2017.07.011.

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.


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