Function of GsMTx4 in advanced atrial fibrillation

2018-08-18

Introduction 

GsMTx4 is a synthetic and biologically active peptide toxin. Its molecular formula is C185H273N49O45S6, with the chemical structure of 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-NH2. Disulfide bonds are between Cys2-Cys17, Cys9-Cys23, and Cys16-Cys30, with Phe34-C-terminal amidation. GsMTx4, a water soluble (solubility in water to 1mg/mL) mechanosensitive and stretch-activated ion channel inhibitor, can block Piezo 1, NaV1.7, TRPC1 and TRPC6 channels.

Pharmacologic action

GsMTx4 is a 34 amino acid peptide originally isolated from the venom of tarantula Grammostola spatulata (Chilean rose), and it belongs to the superfamily of ICK (Inhibitory Cysteine Knot) peptides. Peptide GsMTx4 is a selective inhibitor of stretch-activated cation channels (SACs), working by modifying the gating of SACs, which is different from the traditional lock-and-key model of ligand-protein interactions. There is interaction between GsMTx4 and lipid membranes. The ability of this peptide to bind to membranes is probably the key to its action mechanism. The ability to partition into membranes might also be an essential characteristic of GsMTx4 to be acting as the gating modifiers to SACs.

Function

GsMTx4 is amphipathic and its targets are voltage-gated channels. GsMTx4 blocks cation-selective mechanosensitive ion channels (MSCs) and inhibits atrial fibrillation. In the presence of some vesicles, Trps of GsMTx4 are protected from quenching, with the hydrophobic part being buried in the lipids. It can penetrate into lipid bilayer. Inhibition occurs while GsMTx acts as a gating modifier that changes the channel to the closed state and remains at the protein membrane interface. This was thought to be closely related to the working mechanism as peptide toxin. It suppresses atrial fibrillation and membrane motor of outer hair cells.

Pharmacokinetics and metabolism

The medium toxicity on voltage-gated Na+ channels was reported, including NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7. In addition, the information of inhibiting K+ channels is also studied, such as KV11.1 and KV11.2. However, it does not inhibit KV1.1 (IC50>88μM) and KV1.4 (IC50>85μM). GsMTx4 was reported to block TRPC1, TRPC6 and Piezo 1 channels. GsMTx4 peptide has significant therapeutic implications because it is not degraded by endogenous proteases. It has great potentials in treating atrial fibrillation and can be administered orally. GsMTx4 is analgesic in vivo and shows antimicrobial activity against Gram-negative and Gram-positive bacteria.

References

1. Tedaelli E, Cassulini RR, Silva DF, Clement H, Schiavon E, Zamudio FZ, Odell G, Arcangeli A, Clare JJ, Alagon A, Rodriguez de la Vega RC, Possani LD, Wanke E. Target Promiscuity and heterogeneous effects of tarantula venom peptides affecting Na+ and K+ ion channels. The Journal of Biological Chemistry, 2009, 285, 4130-4142.

2. Spassova MA, Hewavitharana T, Xu W, Soboloff J, Gill DL. A common mechanism underlies stretch activation and receptor activation of TRPC6 channels. PNAS, 2006, 103, 16586-16591.

3. Sugimoto A, Miyazaki A, Kawarabayashi K, Shono M, Akazawa Y, Hasegawa T, Ueda-Yamaguchi K, Kitamura T, Yoshizaki K, Fukumoto S, Iwamoto T. Scientific Report, 2017, 7,17696-17709.

4. Bae C, Sachs F, Gottlieb PA. The mechanosensitive ion channel piezo 1 inhibited by the peptide GxMTx4.

5. Liu Q, Sun B, Zhao J, Wang Q, An F, Hu X, Yang Z, Xu J, Tan M, Li L. Increased piezo 1 channel activity in interstitial cajal-like cells induces bladder hyperactivity by functionally interacting with NCX1 in rats with cyclophosphamide-induced cystitis. Experimental & Molecular Medicine, 2018, 50, 60-75.

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