Mechanical Transduction by Cardiocytes

State University Of New York At Buffalo, Buffalo NY

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Abstract

[unreadable] DESCRIPTION (provided by applicant): All cells have mechanosensitive ion channels (MSCs), biological strain transducers. Their physiological role in the non-specialized sensory tissues, such as the heart, is unknown, but new tools have become available. A peptide originally isolated from tarantula venom, called GsMTx4, acts to specifically block a subset of mechanosensitive ion channels, including channels found in the heart, kidney, glia, skeletal and smooth muscle. The peptide acts as a gating modifier, not a pore plugger, and is active in the mirror image D enantiomer. The peptide(s) appear ready for clinical application in a number of different areas including cardiac arrhythmias and muscular dystrophy. This proposal is a supplemental application to exploit our recent finding regarding SPECIFIC AIM 2 of the parent proposal. The expanded aims are: Aim 1. Replace the charged amino acids of GsMTx4 with neutral and negative amino acids using chemical synthesis. Aim 2. Characterize the peptides by high performance liquid chromatography, circular dichroism, mass spectrometry and solution biochemistry. Aim 3. Conduct electrophysiological assays of peptide inhibition of cloned TRPC1 channels and measure the rates of peptide association and dissociation using substate kinetic analysis. Aim 4. Measure the binding of peptides to lipid membranes using tryptophan fluorescence. Aim 5. Solve the 3D NMR structure of selected peptides. [unreadable] [unreadable]