Calcium Domains around Single and Clustered IP3 Receptors and Their Modulation by Buffers

Rüdiger, Stephan; Nagaiah, Ch.; Warnecke, Gerald; Shuai, Jianwei

doi:10.1016/j.bpj.2010.02.059

Cited by 40 publications

(64 citation statements)

References 30 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%

“…Although this component permitted ref. 37 an impressive fit to single-channel data, detailed simulations with dynamic Ca 2+ feedback showed the time to termination of calcium puffs to be unreasonably long (42,43). This is because the model requires the high Ca 2+ concentration associated with an open channel pore to become inhibited, but can do so only from a closed state where the concentration quickly collapses to resting levels (34).…”

Section: Discussionmentioning

confidence: 99%

“…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%

Section: Discussionmentioning

confidence: 99%

mentioning

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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“…We showed that not only diffusion, but also the presence of Ca 2þ buffers shape the temporal properties of Ca 2þ fluctuations and consequently IP 3 R gating. The influence of Ca 2þ buffers on Ca 2þ signaling has previously been studied, both theoretically (54,(60)(61)(62) and experimentally (63)(64)(65)(66). These studies mainly focused on the influence of mobile and immobile buffers on global Ca 2þ signals, whereas only a very few studies are concerned with the functional role of buffer-dependent Ca 2þ fluctuations (26).…”

Section: Discussionmentioning

confidence: 99%

Exact Stochastic Simulation of a Calcium Microdomain Reveals the Impact of Ca2+ Fluctuations on IP3R Gating

Wieder

Fink

Wegner

2015

Biophysical Journal

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In this study, we numerically analyzed the nonlinear Ca(2+)-dependent gating dynamics of a single, nonconducting inositol 1,4,5-trisphosphate receptor (IP₃R) channel, using an exact and fully stochastic simulation algorithm that includes channel gating, Ca(2+) buffering, and Ca(2+) diffusion. The IP₃R is a ubiquitous intracellular Ca(2+) release channel that plays an important role in the formation of complex spatiotemporal Ca(2+) signals such as waves and oscillations. Dynamic subfemtoliter Ca(2+) microdomains reveal low copy numbers of Ca(2+) ions, buffer molecules, and IP₃Rs, and stochastic fluctuations arising from molecular interactions and diffusion do not average out. In contrast to models treating calcium dynamics deterministically, the stochastic approach accounts for this molecular noise. We varied Ca(2+) diffusion coefficients and buffer reaction rates to tune the autocorrelation properties of Ca(2+) noise and found a distinct relation between the autocorrelation time τac, the mean channel open and close times, and the resulting IP₃R open probability PO. We observed an increased PO for shorter noise autocorrelation times, caused by increasing channel open times and decreasing close times. In a pure diffusion model the effects become apparent at elevated calcium concentrations, e.g., at [Ca(2+)] = 25 μM, τac = 0.082 ms, the IP₃R open probability increased by ≈20% and mean open times increased by ≈4 ms, compared to a zero noise model. We identified the inactivating Ca(2+) binding site of IP₃R subunits as the primarily noise-susceptible element of the De Young and Keizer model. Short Ca(2+) noise autocorrelation times decrease the probability of Ca(2+) association and consequently increase IPvR activity. These results suggest a functional role of local calcium noise properties on calcium-regulated target molecules such as the ubiquitous IP₃R. This finding may stimulate novel experimental approaches analyzing the role of calcium noise properties on microdomain behavior.

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“…Although this component permitted ref. [165] an impressive fit to single channel data, detailed simulations with dynamic Ca 2+ feedback showed the time to termination of calcium puffs to be unreasonably long [157,183]. This is because the model requires the high Ca 2+ concentration associated with an open channel pore to become inhibited, but can do so only from a closed state where the concentration quickly collapses to resting levels [152].…”

Section: 4a) If Openingmentioning

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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Calcium Domains around Single and Clustered IP3 Receptors and Their Modulation by Buffers

Cited by 40 publications

References 30 publications

Emergence of ion channel modal gating from independent subunit kinetics

Emergence of ion channel modal gating from independent subunit kinetics

Exact Stochastic Simulation of a Calcium Microdomain Reveals the Impact of Ca2+ Fluctuations on IP3R Gating

Noise and sensitivity in cell signalling

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