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(Circulation Research. 1995;77:765-772.)
© 1995 American Heart Association, Inc.

Articles

New Insights Into the Gating Mechanisms of Cardiac Ryanodine Receptors Revealed by Rapid Changes in Ligand Concentration

Rebecca Sitsapesan, Richard A.P. Montgomery, Alan J. Williams

From the Department of Cardiac Medicine, The National Heart & Lung Institute, London, UK.

Correspondence to Dr Rebecca Sitsapesan, Department of Cardiac Medicine, The National Heart & Lung Institute, Dovehouse St, London SW3 6LY, UK.

Abstract We have developed a novel technique for incorporation of sheep cardiac sarcoplasmic reticulum (SR) Ca²⁺-release channels into planar phospholipid bilayers in order to investigate changes in [Ca²⁺] on a physiological time scale and have investigated whether the rate of change of cytosolic [Ca²⁺] has a direct effect on the gating of the cardiac SR Ca²⁺-release channel. Vesicles of heavy SR were incorporated into planar phospholipid bilayers painted on glass pipettes, and an established technique for rapid solution exchanges at excised membrane patches was modified to allow solution changes to be made at the bilayer within 10 ms. For a given change in [Ca²⁺], we demonstrate that the open probability (Po) is similar whether the cytosolic [Ca²⁺] is increased rapidly (10 ms) or slowly (1 s) and appears to be no different from the Po measured under steady state conditions that were recorded by using conventional bilayer techniques. We also demonstrate that no desensitization or inactivation occurs at -40 mV when the channel is activated by Ca²⁺ alone or in the presence of other channel activators, ATP or EMD 41000. However, at +40 mV, rapid channel activation followed by inactivation was observed. The probability of such voltage-dependent inactivation appears to depend on the mechanism of channel activation.

Key Words: ryanodine receptors • Ca²⁺-release channels • cardiac excitation-contraction coupling

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