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Original Article

^a From the Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovak Republic 83334
^b Department of Physiology, Texas Tech University Health Sciences Center, Lubbock, Texas 79430
Department of Physiology, Texas Tech University Health Sciences Center, Lubbock, TX 79430.806-743-1512

physg{at}ttuhsc.edu

The local control concept of excitation–contraction coupling in the heart postulates that the activity of the sarcoplasmic reticulum ryanodine receptor channels (RyR) is controlled by Ca²⁺ entry through adjoining sarcolemmal single dihydropyridine receptor channels (DHPRs). One unverified premise of this hypothesis is that the RyR must be fast enough to track the brief (<0.5 ms) Ca²⁺ elevations accompanying single DHPR channel openings. To define the kinetic limits of effective trigger Ca²⁺ signals, we recorded activity of single cardiac RyRs in lipid bilayers during rapid and transient increases in Ca²⁺ generated by flash photolysis of DM-nitrophen. Application of such Ca²⁺ spikes (amplitude 10–30 µM, duration 0.1–0.4 ms) resulted in activation of the RyRs with a probability that increased steeply (apparent Hill slope 2.5) with spike amplitude. The time constants of RyR activation were 0.07–0.27 ms, decreasing with spike amplitude. To fit the rising portion of the open probability, a single exponential function had to be raised to a power n 3. We show that these data could be adequately described with a gating scheme incorporating four sequential Ca²⁺-sensitive closed states between the resting and the first open states. These results provide evidence that brief Ca²⁺ triggers are adequate to activate the RyR, and support the possibility that RyR channels are governed by single DHPR openings. They also provide evidence for the assumption that RyR activation requires binding of multiple Ca²⁺ ions in accordance with the tetrameric organization of the channel protein.

Key Words: cardiac muscle • sarcoplasmic reticulum • ryanodine receptor • calcium signaling • gating model

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