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Channels are not proteins: lessons from mechanosensitive ion channels

F. Sachs, T. Suchyna, P. Gottlieb, Single Molecule Biophysics, SUNY, Buffalo, Buffalo, United States

Mechanosensitive ion channels (MSCs) are ubiquitous, spanning the evolutionary tree. They fall into two classes: those activated by stress in fibrous proteins connected to the channels and those activated by stress in the lipid bilayer. The former are associated with specialized receptors such as cochlear hair cells and the others with cellular receptors not linked to the CNS. This talk addresses the latter class.

Eukaryotes have a common MSC that is cation selective, but none of the members of the family appear to have been cloned. In general, the channels inactivate with time, but the inactivation is not adaptation and it requires an intact cytoskeleton. Activation, on the other hand does not. The only specific inhibitor known for MSCs is a small, basic, pentavalent peptide(Ostrow et al., 2003 ;Oswald et al., 2002) called GsMTx4 isolated from tarantula venom(Suchyna et al., 2000). Its mechanism of action is to shift the gating curve to higher tensions, not to plug the pore. The dogma for peptide/channel interactions claim the mode of action is via a lock and key mechanism that provides specificity and efficacy. However, we synthesized the D enantiomer of GsMTx4 and it works as well as the L form(Suchyna et al., 2004). Thus, the peptide acts specifically on a subclass of eukaryotic MSCs but without a dependence on chirality. This suggests an interaction with the boundary lipids, i.e. the functional unit is not just the protein, but the protein plus the boundary lipids.

(1) Ostrow KL, Mammoser A, Suchyna T, Sachs F, Oswald RE, Kubo S, Chino N, Gottlieb P (2003) cDNA sequence and in vitro folding of GsMTx4, a specific peptide inhibitor of mechanosensitive channels. Toxicon 42:263-274.

(2) Oswald RE, Suchyna TM, McFeeters R, Gottlieb P, Sachs F (2002) Solution structure of peptide toxins that block mechanosensitive ion channels. J Biol Chem 277:34443-34450.

(3) Suchyna T, Tape SE, Koeppe RE, Andersen OS, Sachs F, Gottlieb P (2004) Non-chiral effects of a peptide inhibitor of mechanosensitive channels: evidence for a bilayer-dependent mechanism.

(4) Suchyna TM, Johnson JH, Hamer K, Leykam JF, Gage DA, Clemo HF, Baumgarten CM, Sachs F (2000) Identification of a Peptide Toxin from Grammostola spatulata Spider Venom that Blocks Cation-selective Stretch-activated Channels. J Gen Physiol 115:583-598.