Mechanosensitive ion channels as drug targets.
Mechanically sensitive ion channels (MSCs) are ubiquitous. They exist as two major types: those in specialized receptors that require fibrous proteins to transmit forces to the channel, and those in non-specialized tissues that respond to stress in the lipid bilayer. While few MSCs have been cloned, the existing structures show no sequence or structural homology--an example of convergent evolution. The physiological function of MSCs in many tissues is not known, but they probably arose from the need for cell volume regulation. Recently, a peptide called GsMTx4 was isolated from tarantula venom and is the first specific reagent for mechanosensitive channels. GsMTx4 is a approximately 4 kD peptide with a hydrophobic face opposite a positively charged face. It is active in the D and L forms, and appears non-toxic to mice. GsMTx4 has shown physiological effects on cationic MSCs in heart, smooth muscle, astrocytes, and skeletal muscle. By itself, GsMTx4 can serve as a lead compound or as a potential drug. Its availability opens clinical horizons in the diagnosis and treatment of pathologies including cardiac arrhythmia, muscular dystrophy and glioma.
Gottlieb
Philip A
PA
Center for Molecular Biophysics, 301 Cary Hall, SUNY, Buffalo, NY 14214, USA. philgott@buffalo.edu
Suchyna
Thomas M
TM
Ostrow
Lyle W
LW
Sachs
Frederick
F
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007473:Ion Channels / Q000187:drug effects* / Q000502:physiology; D040542:Mechanotransduction, Cellular / Q000187:drug effects* / Q000502:physiology; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D009136:Muscular Dystrophies / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D013111:Spider Venoms / Q000494:pharmacology* / Q000627:therapeutic use; D013314:Stress, Mechanical
D036341:Intercellular Signaling Peptides and Proteins; D007473:Ion Channels; C411249:MTx4 protein, Grammostola spatulata; D010455:Peptides; D013111:Spider Venoms