Dataset Information

A kinetic model of the inositol trisphosphate receptor based on single-channel data.

ABSTRACT: In many cell types, the inositol trisphosphate receptor is one of the important components controlling intracellular calcium dynamics, and an understanding of this receptor is necessary for an understanding of calcium oscillations and waves. Based on single-channel data from the type-I inositol trisphosphate receptor, and using a Markov chain Monte Carlo approach, we show that the most complex time-dependent model that can be unambiguously determined from steady-state data is one with three closed states and one open state, and we determine how the rate constants depend on calcium. Because the transitions between these states are complex functions of calcium concentration, each model state must correspond to a group of physical states. We fit two different topologies and find that both models predict that the main effect of [Ca(2+)] is to modulate the probability that the receptor is in a state that is able to open, rather than to modulate the transition rate to the open state.

SUBMITTER: Gin E

PROVIDER: S-EPMC2712151 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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A kinetic model of the inositol trisphosphate receptor based on single-channel data.

Gin Elan E Falcke Martin M Wagner Larry E LE Yule David I DI Sneyd James J

Biophysical journal 20090501 10

In many cell types, the inositol trisphosphate receptor is one of the important components controlling intracellular calcium dynamics, and an understanding of this receptor is necessary for an understanding of calcium oscillations and waves. Based on single-channel data from the type-I inositol trisphosphate receptor, and using a Markov chain Monte Carlo approach, we show that the most complex time-dependent model that can be unambiguously determined from steady-state data is one with three clos ...[more]

PMID: 19450477

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Project description:The InsP3R Ca2+ release channel has a biphasic dependence on cytoplasmic free Ca2+ concentration ([Ca2+]i). InsP3 activates gating primarily by reducing the sensitivity of the channel to inhibition by high [Ca2+]i. To determine if relieving Ca2+ inhibition is sufficient for channel activation, we examined single-channel activities in low [Ca2+]i in the absence of InsP3, by patch clamping isolated Xenopus oocyte nuclei. For both endogenous Xenopus type 1 and recombinant rat type 3 InsP3R channels, spontaneous InsP3-independent channel activities with low open probability Po ( approximately 0.03) were observed in [Ca2+]i < 5 nM with the same frequency as in the presence of InsP3, whereas no activities were observed in 25 nM Ca2+. These results establish the half-maximal inhibitory [Ca2+]i of the channel to be 1.2-4.0 nM in the absence of InsP3, and demonstrate that the channel can be active when all of its ligand-binding sites (including InsP3) are unoccupied. In the simplest allosteric model that fits all observations in nuclear patch-clamp studies of [Ca2+]i and InsP3 regulation of steady-state channel gating behavior of types 1 and 3 InsP3R isoforms, including spontaneous InsP3-independent channel activities, the tetrameric channel can adopt six different conformations, the equilibria among which are controlled by two inhibitory and one activating Ca2+-binding and one InsP3-binding sites in a manner outlined in the Monod-Wyman-Changeux model. InsP3 binding activates gating by affecting the Ca2+ affinities of the high-affinity inhibitory sites in different conformations, transforming it into an activating site. Ca2+ inhibition of InsP3-liganded channels is mediated by an InsP3-independent low-affinity inhibitory site. The model also suggests that besides the ligand-regulated gating mechanism, the channel has a ligand-independent gating mechanism responsible for maximum channel Po being less than unity. The validity of this model was established by its successful quantitative prediction of channel behavior after it had been exposed to ultra-low bath [Ca2+].

Dataset Information

A kinetic model of the inositol trisphosphate receptor based on single-channel data.

Publications

A kinetic model of the inositol trisphosphate receptor based on single-channel data.

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