Bilayer-dependent inhibition of mechanosensitive channels by neuroactive peptide enantiomers

• Published in: Nature Vol. 430; no. 6996; pp. 235 - 240
• Main Authors: Andersen, Olaf S, Suchyna, Thomas M, Tape, Sonya E, Koeppe, Roger E, Sachs, Frederick, Gottlieb, Philip A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 08.07.2004; Nature Publishing Group
• Subjects: Amino Acid Sequence; Animal poisons toxicology. Antivenoms; Animals; Araneae; Astrocytes; Biological and medical sciences; Cations - metabolism; Chickens; Electric Conductivity; Gramicidin - metabolism; Grammostola spatulata; Ion Channel Gating - drug effects; Ion Channels - antagonists & inhibitors; Ion Channels - metabolism; Lipid Bilayers - chemistry; Lipid Bilayers - metabolism; Lipids; Mechanotransduction, Cellular - drug effects; Medical sciences; Membranes; Models, Biological; Models, Molecular; Molecular Sequence Data; Myocardium - cytology; Patch-Clamp Techniques; Peptides; Peptides - chemistry; Peptides - pharmacology; Pharmacology; Proteins; Rats; Spider Venoms - chemistry; Spiders; Stereoisomerism; Toxicology; D stereoisomer; Pharmacological activity; Rat; Toxicity; Rodentia; Oral administration; Animal origin; Ionic channel; Biological activity; Isomer; Arachnida; Vertebrata; Mammalia; Arthropoda; Animal; Enantiomer; Venom; Chicken; Aves; Invertebrata; Mechanism of action
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature02743

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 peptides are active, and the effect increases with the degree of hydrophobic mismatch between bilayer thickness and channel length, meaning that GsMTx4 decreases the energy required to deform the boundary lipids adjacent to the channel. GsMTx4 decreases inward SAC single-channel currents but has no effect on outward currents, suggesting it is located within a Debye length of the outer vestibule of the SACs, but significantly farther from the inner vestibule. Likewise, GsMTx4 decreases gA single-channel currents. Our results suggest that modulation of membrane proteins by amphipathic peptides-mechanopharmacology-involves not only the protein itself but also the surrounding lipids. The surprising efficacy of the d form of GsMTx4 peptide has important therapeutic implications, because d peptides are not hydrolysed by endogenous proteases and may be administered orally.