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Department of Cardiac Medicine, National Heart and Lung Institute, University of London.

1. The ryanodine receptor protein of sheep cardiac muscle sarcoplasmic reticulum membranes functions as a ligand-regulated ion channel following solubilization with the zwitterionic detergent CHAPS (3-[(3-cholamidopropyl)-dimethylammonio]-1- propane sulphonate); purification by density gradient centrifugation, reconstitution into proteo-liposomes and incorporation into planar phospholipid bilayers. 2. In the absence of divalent cations, measurable conductance is observed with the group 1a cations and with some larger organic cations. In symmetric 210 mM solutions the following conductance sequence was determined: K+ greater than Rb+ = NH4+ greater than Na+ = Cs+ greater than Li+ much greater than Tris+. 3. Other organic cations, e.g. TEA+, do not produce measurable current under these conditions. 4. Single-channel conductance saturates with increasing ionic activities of K+, Na+ and Li+. Saturation curves are described by Michaelis-Menten kinetic schemes with the following values of maximal conductance and apparent dissociation constant: K+ 900 pS, 19.9 mM; Na+ 516 pS, 17.8 mM; Li+ 248 pS, 9.1 mM. 5. The channel displays only minor differences in permeability amongst the group 1a cations. Relative permeability, monitored under bi-ionic conditions, yields the following sequence: Na+, 1.15 greater than K+, 1.00 = Li+, 0.99 greater than Rb+, 0.87 greater than Cs+, 0.61. Under similar conditions the permeability ratio of NH4+ to K+ was found to be 1.32 and that for Tris+ to K+ was 0.22. 6. The K+ conductance is reduced by low concentrations of the impermeant cation TEA+. Block appears as a smooth reduction in single-channel current amplitude and the degree of block is dependent upon applied voltage. These observations are consistent with a single-site blocking scheme in which TEA+ has access to a site within the voltage drop of the channel from only the cytosolic face of the channel protein and interacts with a site located approximately 90% of the electrical distance across the channel. The zero-voltage dissociation constant for TEA+ block is 50 mM. 7. Single-channel conductance measurements in mixtures of K(+)-Na+ and K(+)-Li+ reveal no anomalous behaviour as the mole fraction of the ions is varied. 8. With monovalent cations as permeant species, the sheep cardiac sarcoplasmic reticulum ryanodine receptor protein functions as a poorly selective, ligand-regulated channel. Under the conditions described here the channel functions as a single-ion pore. It is proposed that discrimination is largely dependent upon the strength of interaction of the permeant ion with a binding site in the conduction pathway.

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