Do Inactivation Mechanisms Rather than Adaptation Hold the Key to Understanding Ryanodine Receptor Channel Gating?

The use of flash photolysis of caged Ca²⁺ to rapidly elevate [Ca²⁺] at the cytosolic face of a cardiac ryanodine receptor (RyR) channel reconstituted into a bilayer gives rise to a rapid increase in open probability (Po; Györke and Fill 1993). This is followed by a decline in Po, which occurs much more slowly (τ = 1.3 s). After the decline in Po, the channels can be reactivated by a second Ca²⁺ stimulus. These results led to the suggestion that RyR channels can adapt to a maintained Ca²⁺ stimulus. The report was of great interest for two main reasons.

First, the concept that Ca²⁺-induced Ca²⁺ release (CICR) was a process that was smoothly graded and dependent on the magnitude of the trigger rather than an all-or-nothing process was difficult to...