Inositol 1,4,5-trisphosphate receptors in the endoplasmic reticulum: A single-channel point of view

Mak, Don‐On Daniel; Foskett, J. Kevin

doi:10.1016/j.ceca.2014.12.008

Cited by 73 publications

(67 citation statements)

References 80 publications

(169 reference statements)

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“…Under fixed ligand conditions, the type 1 IP 3 R gates in three modes that are characterized by high, intermediate, and low open probability. The within-mode open probabilities are approximately ligand independent, whereas the proportion of time spent in each mode is regulated by the IP 3 and Ca 2+ concentration (7,30), leading to the well-described bell-shaped open probability curve (28,31,32). In contrast to the slow switching between modes, the channel exhibits individual opening and closing events of millisecond durations and responds rapidly to changing ligand concentrations (29).…”

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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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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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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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“…[8]). Several configurations can be achieved, including nucleus-attached, luminal-side-out, cytoplasmic-side-out, and nucleoplasmic-side-out (SI Ref.…”

Section: Endoplasmic Reticulummentioning

confidence: 99%

“…IP3-Rs are the essential signal transduction player in the phospholipase C (PLC) pathway that is stimulated by numerous neurotransmitters and hormones (Mak and Foskett; Ref. [8] in this SI). Additionally, intracellular transport of other ions such as Na + and K + regulates organellar membrane potential and luminal ionic homeostasis, which are known to affect Ca 2+ signaling indirectly [2].…”

Section: Introductionmentioning

confidence: 99%

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Organellar channels and transporters

Martinoia

Szabó

2015

Cell Calcium

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Decades of intensive research has led to the discovery of most plasma membrane ion channels and transporters and the characterization of their physiological functions. In contrast, although over 80% of transport processes occur inside the cells, the ion flux mechanisms across intracellular membranes (the endoplasmic reticulum, Golgi apparatus, endosomes, lysosomes, mitochondria, chloroplasts, and vacuoles) are difficult to investigate and remain poorly understood. Recent technical advances in super-resolution microscopy, organellar electrophysiology, organelle-targeted fluorescence imaging, and organelle proteomics have pushed a large step forward in the research of intracellular ion transport. Many new organellar channels are molecularly identified and electrophysiologically characterized. Additionally, molecular identification of many of these ion channels/transporters has made it possible to study their physiological functions by genetic and pharmacological means. For example, organellar channels have been shown to regulate important cellular processes such as programmed cell death and photosynthesis, and are involved in many different pathologies. This Special Issue (SI) on Organellar Channels and Transporters aims to provide a forum to discuss the recent advances and to define the standard and open questions in this exciting and rapidly-developing field. Along this line, a new Gordon Research Conference dedicated to the multidisciplinary study of intracellular membrane transport proteins will be launched this coming summer.

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“…A detailed understanding of this important feature of IP 3 R behavior is therefore crucial for unraveling the complexity of Ca 2+ signaling, and its role in cell function and disease. and Ca 2+ concentration [88,109]. This regulation of gating modes leads to the well-described…”

Section: Introductionmentioning

confidence: 93%

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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Inositol 1,4,5-trisphosphate receptors in the endoplasmic reticulum: A single-channel point of view

Cited by 73 publications

References 80 publications

Emergence of ion channel modal gating from independent subunit kinetics

Emergence of ion channel modal gating from independent subunit kinetics

Organellar channels and transporters

Noise and sensitivity in cell signalling

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