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Voltage-Sensitive Equilibrium between Two States within a Ryanoid-Modified Conductance State of the Ryanodine Receptor Channel

Bhavna Tanna ^*, William Welch , Luc Ruest , John L. Sutko  and Alan J. Williams ^*

^* Cardiac Medicine, National Heart & Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom; Department of Biochemistry, University of Nevada School of Medicine, Reno, Nevada; Department of Chemistry, University of Sherbrooke, Quebec, Canada; and Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada

Correspondence: Address reprint requests to Alan J. Williams, Fax: 44-20-7823-3392; E-mail: a.j.williams{at}ic.ac.uk.

We have investigated the influence of transmembrane holding potential on the kinetics of interaction of a cationic ryanoid, 8ß-amino-9-hydroxyryanodine, with individual ryanodine receptor (RyR) channels and on the functional consequences of this interaction. In agreement with previous studies involving cationic, neutral, and anionic ryanoids, both rates of association and dissociation of the ligand are sensitive to transmembrane potential. A voltage-sensitive equilibrium between high- and low-affinity forms of the receptor underlies alterations in rates of association and dissociation of the ryanoid. The interaction of 8ß-amino-9-hydroxyryanodine with RyR influences the rate of cation translocation through the channel. With this ryanoid bound, the channel fluctuates between two clearly resolved subconductance states ( and ß). We interpret this observation as indicating that with 8ß-amino-9-hydroxyryanodine bound, the pore of the RyR channel exists in two essentially isoenergetic conformations with differing ion-handling properties. The equilibrium between the - and ß-states of the RyR-8ß-amino-9-hydroxyryanodine complex is sensitive to transmembrane potential. However, the mechanisms determining this equilibrium differ from those responsible for the voltage-sensitive equilibrium between high- and low-affinity forms of the receptor.

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