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

Ullah, Ghanim; Ullah, Aman

doi:10.1007/s10867-016-9419-2

Cited by 10 publications

(10 citation statements)

References 38 publications

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“…While inferring parameters related to the single-channel behavior (e.g. [IP 3 ] and channel flux) from localized Ca 2+ signals ( μ m-sized events called puffs) has been demonstrated before [105, 106], this to our knowledge is the first exhibition of estimating such parameters from the whole-cell Ca 2+ signals. We are also not aware of any other study directly fitting a whole-cell Ca 2+ model to TIRF signals.…”

Section: Discussionmentioning

confidence: 82%

Data-driven modeling of mitochondrial dysfunction in Alzheimer's disease

et al. 2018

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Intracellular accumulation of oligomeric forms of β amyloid (Aβ) are now believed to play a key role in the earliest phase of Alzheimer's disease (AD) as their rise correlates well with the early symptoms of the disease. Extensive evidence points to impaired neuronal Ca homeostasis as a direct consequence of the intracellular Aβ oligomers. However, little is known about the downstream effects of the resulting Ca rise on the many intracellular Ca-dependent pathways. Here we use multiscale modeling in conjunction with patch-clamp electrophysiology of single inositol 1,4,5-trisphosphate (IP) receptor (IPR) and fluorescence imaging of whole-cell Ca response, induced by exogenously applied intracellular Aβ oligomers to show that Aβ inflicts cytotoxicity by impairing mitochondrial function. Driven by patch-clamp experiments, we first model the kinetics of IPR, which is then extended to build a model for the whole-cell Ca signals. The whole-cell model is then fitted to fluorescence signals to quantify the overall Ca release from the endoplasmic reticulum by intracellular Aβ oligomers through G-protein-mediated stimulation of IP production. The estimated IP concentration as a function of intracellular Aβ content together with the whole-cell model allows us to show that Aβ oligomers impair mitochondrial function through pathological Ca uptake and the resulting reduced mitochondrial inner membrane potential, leading to an overall lower ATP and increased production of reactive oxygen species and HO. We further show that mitochondrial function can be restored by the addition of Ca buffer EGTA, in accordance with the observed abrogation of Aβ cytotoxicity by EGTA in our live cells experiments.

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Section: Discussionmentioning

confidence: 82%

Data-driven modeling of mitochondrial dysfunction in Alzheimer's disease

et al. 2018

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“…Repetitive calcium events (e.g., calcium puffs and oscillations) may exhibit various frequencies (23,36), which have been best characterized by the distributions of IPI and interspike interval (17,23). Previous studies have primarily focused on how the IP 3 R parameters vary the puff frequency (25,(37)(38)(39)(40). However, the inverse problem potentially provides a different way of estimating the important IP 3 R parameters.…”

Section: Discussionmentioning

confidence: 99%

Mapping Interpuff Interval Distribution to the Properties of Inositol Trisphosphate Receptors

Cao

Falcke

Sneyd

2017

Biophysical Journal

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Tightly clustered inositol trisphosphate receptors (IPRs) control localized Ca liberation from the endoplasmic reticulum to generate repetitive Ca puffs. Distributions of the interpuff interval (IPI), i.e., the waiting time between successive puffs, are found to be well characterized by a probability density function involving only two parameters, λ and ξ, which represent the basal rate of puff generation and the recovery rate from refractoriness, respectively. However, how the two parameters depend on the kinetic parameters of single IPRs in a cluster is still unclear. In this article, using a stochastic puff model and a single-channel data-based IPR model, we establish the dependencies of λ and ξ on two important IPR model parameters, IP concentration ([IP]) and the recovery rate from Ca inhibition (r). By varying [IP] and r in physiologically plausible ranges, we find that the ξ-λ plane is comprised of only two disjoint regions, a biologically impermissible region and a region where each parameter set (ξ, λ) can be caused by using two different combinations of [IP] and r. The two combinations utilize very different mechanisms to maintain the same IPI distribution, and the mechanistic difference provides a way of identifying IPR kinetic parameters by observing properties of the IPI.

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“…We also process fluorescence data from a simulated cluster composed of 10 IP 3 R Ca 2+ channels. Details about simulating a single cluster have been published before (26,29,30). Ca 2+ concentration on the cytosolic side of the cluster was controlled by diffusion, flux through IP 3 Rs, free stationary buffers, mobile buffers, and imaging dye.…”

Section: Data Recordsmentioning

confidence: 99%

TraceSpecks: a software for automated idealization of noisy patch-clamp and imaging data

Shah

Demuro

Mak

et al. 2018

Preprint

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Experimental records of single molecules or ion channels from fluorescence microscopy and patch-clamp electrophysiology often include high-frequency noise and baseline fluctuations that are not generated by the system under investigation and have to be removed. Moreover, multiple channels or conductance levels can be present at a time in the data that need to be quantified to accurately understand the behavior of the system. Manual procedures for removing these fluctuations and extracting conducting states or multiple channels are laborious, prone to subjective bias, and hinder the processing of often very large data-sets. We introduce a maximum likelihood formalism for separating signal from a noisy and drifting background such as fluorescence traces from imaging of elementary Ca 2+ release events called puffs arising from clusters of channels and patch-clamp recordings of ion channels. Parameters such as the number of open channels or conducting states, noise level, and background signal can all be optimized using the expectation-maximization (EM) algorithm. We implement our algorithm following the Baum-Welch approach to EM in the portable java language with a user-friendly graphical interface and test the algorithm on both synthetic and experimental data from patch-clamp electrophysiology of Ca 2+ channels and fluorescence microscopy of a cluster of Ca 2+ channels and Ca 2+ channels with multiple conductance levels. The resulting software is accurate, fast, and provides detailed information usually not available through manual analysis. Options for visual inspection of the raw and processed data with key parameters, and exporting a range of statistics such as the mean open probabilities, mean open times, mean close times, and dwell time distributions for different number of channels open or conductance levels, amplitude distribution of all opening events, and number of transitions between different number of open channels or conducting levels in asci format with a single click are provided.

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

Cited by 10 publications

References 38 publications

Data-driven modeling of mitochondrial dysfunction in Alzheimer's disease

Data-driven modeling of mitochondrial dysfunction in Alzheimer's disease

Mapping Interpuff Interval Distribution to the Properties of Inositol Trisphosphate Receptors

TraceSpecks: a software for automated idealization of noisy patch-clamp and imaging data

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