Electrostatic mechanisms underlie neomycin block of the cardiac ryanodine receptor channel (RyR2)

Biophysical Journal
Fiona Mead, Alan J Williams

Abstract

Neomycin is a large, positively charged, aminoglycoside antibiotic that has previously been shown to induce a voltage-dependent substate block in the cardiac isoform of the ryanodine receptor (RyR2). It was proposed that block involved an electrostatic interaction between neomycin and putative regions of negative charge in both the cytosolic and luminal mouths of the pore. In this study, we have attempted to screen charge by increasing potassium concentration in single-channel experiments. Neomycin block is apparent at both cytosolic and luminal faces of the channel in all K+ concentrations tested and alterations in K+ concentration have no effect on the amplitudes of the neomycin-induced substates. However, the kinetics of both cytosolic and luminal block are sensitive to changes in K+ concentration. In both cases increasing the K+ concentration leads to an increase in dissociation constant (KD). Underlying these changes are marked increases in rates of dissociation (k(off)), with little change in rates of association (k(on)). The increase in k(off) is more marked at the luminal face of the channel. Changes in K+ concentration also result in alterations in the voltage dependence of block. We have interpreted these data as supp...Continue Reading

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Mar 28, 2002·Biophysical Journal·Fiona Mead, Alan J Williams

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Citations

Mar 1, 2006·The Journal of General Physiology·Joachim Scholz-StarkeFranco Gambale
May 7, 2010·American Journal of Physiology. Cell Physiology·Thirumalini VaithianathanAlejandro M Dopico
Dec 18, 2009·PloS One·Paula L Diaz-Sylvester, Julio A Copello
Oct 20, 2009·Journal of Molecular and Cellular Cardiology·Fredrick A HilliardBjörn C Knollmann
Oct 18, 2005·Biochemical and Biophysical Research Communications·Nicholas PughAlan J Williams
Feb 23, 2019·MSphere·Mikal A Woods AcevedoJulie K Pfeiffer

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