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The Interaction of an Impermeant Cation with the Sheep Cardiac RyR Channel Alters Ryanoid Association

Cardiac Medicine, National Heart & Lung Institute, Imperial College London, Guy Scadding Building, Dovehouse Street, London, United Kingdom (B.T., A.J.W.); Departments of Biochemistry (W.W.) and Pharmacology (J.L.S.), University of Nevada School of Medicine, Reno, Nevada; and Department of Chemistry, University of Sherbrooke, Quebec, Canada (L.R.)

In previous studies, we have demonstrated that the interaction of ryanoids with the sarcoplasmic reticulum Ca²⁺-release channel [ryanodine receptor (RyR)] incorporated into planar lipid bilayers reduced the effectiveness of tetraethylammonium (TEA⁺) as a blocker of K⁺ translocation (J Gen Physiol 117: 385-393, 2001). In the current study, we investigated both the effect of TEA⁺ on [³H]ryanodine binding and the actions of this impermeant cation on the interaction of the reversible ryanoid 21-amino-9-hydroxyryanodine with individual, voltage-clamped RyR channels. A dose-dependent inhibition of [³H]ryanodine binding was observed in the presence of TEA⁺, suggesting that the cation and alkaloid compete for access to a common site of interaction. Single channel studies gave further insights into the mechanism of the competition between the two classes of ligands. TEA⁺ decreases the association rate of 21-amino-9-hydroxyryanodine with its receptor, whereas the dissociation rate of the ryanoid from the channel was unaffected. Our results demonstrate that TEA⁺ inhibits both K⁺ translocation through RyR, and ryanoid interaction at the high affinity ryanodine site on the channel. These actions involve binding of TEA⁺ to different, but weakly interacting, sites in the RyR channel.

Address correspondence to: Professor Alan J. Williams, Cardiac Medicine, National Heart and Lung Institute, Imperial College London, Guy Scadding Building, Dovehouse Street, London, SW3 6LY. UK. E-mail: a.j.williams{at}imperial.ac.uk