Keizer, Levine, 1996

Model Structure

The ryanodine receptor (RyR) from cardiac cells and skeletal muscle undergoes a Ca²⁺-dependent process called adaptation. Adaptation occurs during the slow, spontaneous decrease in the open probability of a channel after it has been rapidly activated by a pulse of cytosolic calcium ([Ca²⁺]_i). RyR activation occurs within milliseconds, whereas inactivation occurs on a timescale of a few seconds. The RyR is said to have "adapted" during inactivation because a subsequent increase in [Ca²⁺]_i produces a nearly identical rise in the open probability.

In their 1996 paper, Joel Keizer and Leslie Levine develop a simplified model that mimics the "adaptation" of the RyR, and they investigate its significance for Ca²⁺-induced Ca²⁺ release and Ca²⁺ oscillations in cardiac cells. The mechanism used to mimic adaptation of the RyR is shown schematically in the figure below. States C1 and C2 are closed states and O1 and O2 are open states. Transitions from C1 to O1 and from O1 to O2 are assumed to be Ca²⁺-dependent. These steps correspond to the phenomenon of Ca²⁺-induced Ca²⁺ release (CICR). To analyse the mechanism in the figure , Keizer and Levine translated the schematic diagram into kinetic equations. In addition, they test these equations in a closed-cell kinetic model, and they find that RyR adaptation can cause Ca²⁺ oscillations. However, in an open-cell, CICR, not RyR adaptation, produces Ca²⁺ oscillations.

The complete original paper reference is cited below:

Ryanodine Receptor Adaptation and Ca²⁺-Induced Ca²⁺ Release-Dependent Ca²⁺ Oscillations, Joel Keizer and Leslie Levine, 1996, Biophysical Journal , 71, 3477-3487. PubMed ID: 8968617

The raw CellML description of the kinetic model of cardiac RyR adaptation can be downloaded in various formats as described in .

Schematic diagram of transitions among the four states of the RyR used to describe adaptation. States C1 and C2 are closed states and O1 and O2 represent open states, assumed to have the same single-channel conductance. The k are rate constants: only steps a and b are Ca²⁺ dependent.