Dawson, Lea, Irvine, 2003

Model Status

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Model Structure

The release of Ca²⁺ from intracellular stores via InsP₃ receptors displays unusual kinetics. It has been shown that successive additions of low concentrations of InsP₃ causes successive rapid transients of Ca²⁺ release. Two hypotheses have been put forward to explain this phenomenon, either:

Cells contain a series of Ca²⁺ stores of various sensitivities to InsP₃, such that at any given concentration of InsP₃, only some stores will release their Ca²⁺, whilst others remain intact. This is also known as the all-or-nothing model; or
InsP₃ receptors are able to adapt to a particular InsP₃ concentration, such that at a given [InsP₃], all the Ca²⁺ stores partially empty. Because partial emptying induces faster cycling of Ca²⁺ across the store membrane via the SERCA pump, this theory is also known as the steady-state model.

There are sets of experimental data in support of both explanations. The two theories require very different mechanisms. The all-or-nothing model not only requires differing sensitivities of stores to InsP₃, but also a high degree of cooperativity such that a small range of InsP₃ concentrations will empty a particular store whilst leaving others unaffected. Differences in sensitivity could be due to structural differences, differences in InsP₃ density, intracellular cell environment, or luminal [Ca²⁺]. In contrast, the steady-state model seems to require complex, adaptive kinetic changes in the receptor. Mathematical steady-state models have been developed and in general they involve effects of Ca²⁺ binding to sites within the channel or to sites in the channel mouth, although there is also evidence that the InsP₃ receptor can show adaptive behaviour.

Models of adaptive behaviour at the single channel level have been developed for the structurally homologous ryanodine receptor. It has been suggested that similar mechanisms account for the behaviour of the InsP₃ receptor. Using the Sachs et al. ryanodine receptor model as a foundation, Dawson et al. develop such a model. They begin with a relatively simple situation with no Ca²⁺ fluxes (see ), to more complex situations which account for the positive and negative feedback from Ca_(cyt), and the inactivation of the receptor in the presence of Ca²⁺ (see and ). This final model is an adaptive model of the InsP₃ receptor that can show either all-or-nothing or steady-state behaviour, depending on the experimental conditions. The model suggests that the receptor has two interconvertible conformational states: one that rapidly binds InsP₃ but has a low affinity for the ligand, while the other state binds slowly but with a high affinity.

The models have been described here in CellML (the raw CellML description of the Dawson et al. 2003 models can be downloaded in various formats as described in ).

The complete original paper reference is cited below:

Kinetic model of the inositol trisphosphate receptor that shows both steady-state and quantal patterns of Ca²⁺ release from intracellular stores, Alan P. Dawson, Edward J. A. Lea, and Robin F. Irvine, 2003, Biochemical Journal , 370, 621-629. PubMed ID: 12479792

Scheme 1: An adapting model of the InsP₃ receptor.

Scheme 2: An adapting model of the InsP₃ receptor which includes feedback effects of Ca²⁺ near the channel mouth.

Scheme 3: Adaptive channel model based on the occupation of one InsP₃ binding site being required to open the channel.