Perspective Questions about Adaptation in Ryanodine Receptors

The proposal of adaptation in individual ryanodine receptor (RyR)/Ca 2 1 release channels (Györke and Fill, 1993) has been an exciting concept that has stimulated widespread consideration of the properties and mechanisms involved in the activation and termination of Ca 2 1 release in muscle and other cells. Here, we consider what adaptation of individual RyRs is defined to mean and examine the evidence for its existence in the light of the recent reappraisal of the stimulus used in the original experiments. We further discuss the findings of other single-channel studies, as well as in vivo studies on Ca 2 1 release designed to test a possible role of adaptation, and conclude that there are inconsistencies in the adaptation model of RyR regulation. In an attempt to resolve the issue, and to obtain insights into the fascinating dynamic responses of a RyR to large, transient Ca 2 1 stimuli, which may be fundamental for RyR function in vivo, we present an alternative model to explain the data of Györke and colleagues.