Modulation of Elementary Calcium Release Mediates a Transition from Puffs to Waves in an IP3R Cluster Model

Rückl, Martin; Parker, Ian; Marchant, Jonathan S.; Chamakuri, Nagaiah; Johenning, Friedrich W.; Rüdiger, Stephan

doi:10.1371/journal.pcbi.1003965

Cited by 26 publications

(35 citation statements)

References 59 publications

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“…We assume that each of the four subunits that compose the channel are identical and independent and have a single active state that becomes accessible after ligand binding. Previous DYK schemes assume that the channel opens when at least three of four subunits are active (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45). This yields a channel with multiple open states, consistent with experimental observations (37).…”

Section: Resultssupporting

confidence: 73%

“…Stochastic implementations of the classic De Young-Keizer (DYK) model assume four independent subunits and explicitly incorporate ligand binding and conformational change (33,34). Variants of this scheme have been widely used in studies of the IP 3 R and Ca 2+ dynamics (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45), although none exhibit modal gating. This raises the question of whether this intuitive, bottom-up approach is compatible with current knowledge of IP 3 R regulation.…”

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confidence: 99%

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Emergence of ion channel modal gating from independent subunit kinetics

Bicknell

Goodhill

2016

Proc. Natl. Acad. Sci. U.S.A.

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Many ion channels exhibit a slow stochastic switching between distinct modes of gating activity. This feature of channel behavior has pronounced implications for the dynamics of ionic currents and the signaling pathways that they regulate. A canonical example is the inositol 1,4,5-trisphosphate receptor (IP3R) channel, whose regulation of intracellular Ca2+ concentration is essential for numerous cellular processes. However, the underlying biophysical mechanisms that give rise to modal gating in this and most other channels remain unknown. Although ion channels are composed of protein subunits, previous mathematical models of modal gating are coarse grained at the level of whole-channel states, limiting further dialogue between theory and experiment. Here we propose an origin for modal gating, by modeling the kinetics of ligand binding and conformational change in the IP3R at the subunit level. We find good agreement with experimental data over a wide range of ligand concentrations, accounting for equilibrium channel properties, transient responses to changing ligand conditions, and modal gating statistics. We show how this can be understood within a simple analytical framework and confirm our results with stochastic simulations. The model assumes that channel subunits are independent, demonstrating that cooperative binding or concerted conformational changes are not required for modal gating. Moreover, the model embodies a generally applicable principle: If a timescale separation exists in the kinetics of individual subunits, then modal gating can arise as an emergent property of channel behavior.

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Section: Resultssupporting

confidence: 73%

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confidence: 99%

Emergence of ion channel modal gating from independent subunit kinetics

Bicknell

Goodhill

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…3a, open circles) and longer duration (Fig. 3a, filled whole cell waves and oscillations [29,31]. Similarly, the average rate of channel openings (Fig.…”

Section: Resultsmentioning

confidence: 66%

“…5). Although we do not simulate whole-cell Ca 2+ waves and oscillations, these events with large amplitude and longer duration occurring at high frequency would most likely trigger global Ca 2+ signals [31]. Consistent with the observations during single channel patch-clamp experiments [4] and recent modeling study [14], our results show that the transition of the channel behavior from gating predominantly in low mode during small events to gating in the intermediate and high modes during large events is due to the significant decrease in τ c with a slight increase in τ o of the channel (Figs.…”

Section: Discussionmentioning

confidence: 99%

Mode switching of Inositol 1,4,5-trisphosphate receptor channel shapes the Spatiotemporal scales of Ca2+ signals

Ullah

2016

J Biol Phys

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“…Large scale phenomena such as whole-cell calcium oscillations [60], and the propagation of waves [150], have also been very elegantly described in terms of underlying stochastic activity, diffusion coupling and feedback.…”

Section: Future Study Of Calcium Dynamicsmentioning

confidence: 99%

Noise and sensitivity in cell signalling

Bicknell¹

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The ability of cells to receive and process chemical information is fundamental to the function of biological systems. Cell responses to salient chemical cues are characteristically reliable and precise, a striking example being the guidance of axons to their targets during brain development. However, chemical signalling pathways are subject to multiple sources of unavoidable noise, due to the random nature of molecular motion and interactions. This suggests that cellular systems may be optimised for transduction of noisy signals, which provides a guiding principle for understanding cell function at a biophysical level. In pursuit of this idea, we study three model problems, motivated by sensing and signalling in axon guidance. Our approach is to construct mathematical models, and through analysis and simulation, extract general principles and hypotheses about the quantitative nature of biological noise and mechanisms for sensitive chemosensation.First, we quantify the physical limits of chemosensation imposed by the random thermal motion of the molecules that need to be counted. In particular, we show how this depends on the dimension and spatial extent of the domain of diffusion. Although recurrent diffusion in 1d and 2d is detrimental to measurement precision, we find these effects are suppressed when sensing is performed within a confined space. Second, we study the stochastic behaviour of the inositol 1,4,5-trisphosphate receptor ion channel, which couples receptor activity at the membrane to the downstream calcium response that regulates axon growth and turning. By modelling the basic biophysical events that control ion channel opening, we introduce a new principle for understanding the origin of the multiple gating modes observed in single channel recordings. Third, we examine the finely-tuned response of dorsal root ganglia neurons to very shallow neurotrophin gradients. We show how paracrine signalling within the ganglion could explain this extreme sensitivity, as well as the currently unexplained biphasic dose response of many axon growth and guidance cues.Overall, this thesis gives new quantitative insights into chemical signalling in biological systems, across multiple stages of processing and spatial scales. Our models make testable predictions to motivate new experiments, and provide a strong foundation for further theoretical and computational study in both axon guidance and broader domains of biophysics.iii

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Modulation of Elementary Calcium Release Mediates a Transition from Puffs to Waves in an IP3R Cluster Model

Cited by 26 publications

References 59 publications

Emergence of ion channel modal gating from independent subunit kinetics

Emergence of ion channel modal gating from independent subunit kinetics

Mode switching of Inositol 1,4,5-trisphosphate receptor channel shapes the Spatiotemporal scales of Ca2+ signals

Noise and sensitivity in cell signalling

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