Bilayer-dependent inhibition of mechanosensitive channels by neuroactive peptide enantiomers

  title={Bilayer-dependent inhibition of mechanosensitive channels by neuroactive peptide enantiomers},
  author={Thomas M. Suchyna and Sonya E. Tape and Roger E. Koeppe and Olaf S. Andersen and Frederick Sachs and Philip A. Gottlieb},
The peptide GsMTx4, isolated from the venom of the tarantula Grammostola spatulata, is a selective inhibitor of stretch-activated cation channels (SACs). The mechanism of inhibition remains unknown; but both GsMTx4 and its enantiomer, enGsMTx4, modify the gating of SACs, thus violating a trademark of the traditional lock-and-key model of ligand–protein interactions. Suspecting a bilayer-dependent mechanism, we examined the effect of GsMTx4 and enGsMTx4 on gramicidin A (gA) channel gating. Both… 

GsMTx4: Mechanism of Inhibiting Mechanosensitive Ion Channels.

Concentration dependent effect of GsMTx4 on mechanosensitive channels of small conductance in E. coli spheroplasts

The spider peptide GsMTx4 exhibits a biphasic response in which peptide concentration determines inhibition or potentiation of activity in prokaryotic MS channels, showing the effect of different concentrations of extracellular Gs MTx4 on MS channels of small conductance, MscS and MscK in the cytoplasmic membrane of wild-type E. coli spheroplasts using the patch-clamp technique.

Two types of peptides derived from the neurotoxin GsMTx4 inhibit a mechanosensitive potassium channel by modifying the mechanogate

The neuropeptide GsMTx4 inhibits a mechanosensitive BK channel through the voltage-dependent modification specific to mechano-gating

The results provide common mechanisms of peptide actions on MS channels and may give clues to therapeutic suppression of cardiac arrhythmias caused by excitatory currents through MS channels under hyper-mechanical stress in the heart.

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

  • H. JungP. Kim J. Kim
  • Biology, Chemistry
    Biochemical and biophysical research communications
  • 2006

Atomistic Molecular Simulation of Gating Modifier Venom Peptides – Two Binding Modes and Effects of Lipid Structure

Simulation results support the view that the channel/GsMTx4 (or HaTx)/lipids make a tertiary complex crucial to the effectiveness of the toxin and therefore binding of the toxins to channels occurs only in the presence of lipid molecules with appropriate structures.

The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4.

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.

Effect of Gating Modifier Toxins on Membrane Thickness: Implications for Toxin Effect on Gramicidin and Mechanosensitive Channels

A protocol is developed that allows the spontaneous assembly of a polypeptide toxin into membranes in atomistic molecular dynamics simulations of tens of nanoseconds and is found that the bilayer is about 2 Å thinner upon the binding of a GsMTx4 monomer.



Solution Structure of Peptide Toxins That Block Mechanosensitive Ion Channels*

The first structures of any kind known to interact specifically with MSCs, GsMTx-4 and GsMtx-2 are inhibitor cysteine knot peptides isolated from venom of the tarantula and the dominant feature of the two structures is a hydrophobic patch, utilizing most of the aromatic residues and surrounded with charged residues.

Identification of a Peptide Toxin from Grammostola spatulata Spider Venom That Blocks Cation-Selective Stretch-Activated Channels

A 35 amino acid peptide toxin of the inhibitor cysteine knot family that blocks cationic stretch-activated ion channels is identified and implicates SACs in volume regulation.

cDNA sequence and in vitro folding of GsMTx4, a specific peptide inhibitor of mechanosensitive channels.

Genistein can modulate channel function by a phosphorylation-independent mechanism: importance of hydrophobic mismatch and bilayer mechanics.

Results strongly suggest that genistein alters bilayer mechanical properties, which in turn modulates channel function, and are likely to apply to other pharmacological reagents and membrane proteins.

Thermodynamics of mechanosensitivity

A general thermodynamic formalism is constructed that provides the basis for the analysis of the behaviour of mechanosensitive channels in lipids of different geometric and chemical properties such as the hydrophobic mismatch at the boundary between the protein and lipid or the effects of changes in the bilayer intrinsic curvature caused by the adsorption of amphipaths.

Lysophospholipids modulate channel function by altering the mechanical properties of lipid bilayers

Results show that LPLs alter gramicidin channel function by altering the membrane deformationEnergy, and that the changes in deformation energy can be related to the molecular "shape" of the membrane-modifying compounds.

Kinetics of gramicidin channel formation in lipid bilayers: transmembrane monomer association.

Results indicate that the hydrophobic gramicidins are surprisingly membrane impermeant, a conclusion that was confirmed in experiments in which gA was added asymmetrically and symmetrically to preformed bilayers.

Physical principles underlying the transduction of bilayer deformation forces during mechanosensitive channel gating

It is proposed that the mechanism of mechanotransduction in MS channels is defined by both local and global asymmetries in the transbilayer pressure profile at the lipid–protein interface.

Phospholipase A2 as a mechanosensor.

On the helix sense of gramicidin A single channels

An optically reversed analogue of gramicidin A is synthesized, to test whether it forms channels that have the same handedness as channels formed by gramicIDin M−, and it is found that GramicidIn A− channels are therefore left‐handed, and natural gramicilipid bilayers are right‐handed β6.3‐helical dimers.