Endogenous inhibitors of InsP3-induced Ca2+ release in neuroblastoma cells

Watras, J; Fink, Charles C.; Loew, Leslie M.

doi:10.1016/j.brainres.2005.06.091

Cited by 4 publications

(5 citation statements)

References 43 publications

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“…The modelling predicted a remarkable initial stimulated increase in PIP 2 concomitant with activation of PLC‐mediated PIP 2 hydrolysis. Interestingly, the sensitivity of the Ins P 3 R in these cells is an order of magnitude lower than in non‐neuronal cells (Watras et al 2005). Thus, the ability of these cells to replenish PIP 2 as it is being hydrolysed makes it possible for the cell to produce sufficient Ins P 3 to produce a robust calcium release.…”

Section: Pip2 Dynamics In Neuroblastoma Cells – Stimulated Productionmentioning

confidence: 87%

Where does all the PIP₂ come from?

Loew

2007

The Journal of Physiology

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Despite its very low concentration in the plasma membrane, PIP 2 is the precursor for the important second messenger InsP 3 and, independently, is a key modulator of membrane signalling molecules such as ion channels. However, it has been difficult to determine the spatial and temporal characteristics of PIP 2 and InsP 3 during a cell signalling event. Our laboratory used bradykinin stimulation of N1E-115 neuroblastoma cells to infer the InsP 3 dynamics from calcium imaging studies, biochemical analysis and InsP 3 uncaging. We have used computational modelling with Virtual Cell to help analyse and interpret experimental data on the details of the calcium release process as well as to build a comprehensive image-based model of agonist-induced calcium release in a neuronal cell. These data provided a constraint for the further investigation of how low levels of cellular PIP 2 could provide sufficient InsP 3 for calcium release. Using biochemical assays, quantitative imaging of GFP-based probe translocation and computational analysis, it was shown that PIP 2 synthesis is stimulated concomitant with its hydrolysis. This mechanism should be important not just for consideration of PIP 2 as a precursor of InsP 3 , but for any pathway that can be directly or indirectly modulated by PIP 2 .

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Section: Pip2 Dynamics In Neuroblastoma Cells – Stimulated Productionmentioning

confidence: 87%

Where does all the PIP₂ come from?

Loew

2007

The Journal of Physiology

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“…One possible explanation for this apparent contradiction is, if the magnitudes of InsP 3 increases are much larger in the neuronal cells used in the Nelson study than those observed in HEK293 cells. This is not an unreasonable assumption, since N1E-115 neuroblastoma cells require much higher InsP 3 increases to induce Ca 2+ signaling than other cell types [ 37 ]. In search of an explanation for this unique feature, Watras et al has identified a protein in neurons that binds the InsP 3 receptor to significantly decrease its InsP 3 sensitivity [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…This is not an unreasonable assumption, since N1E-115 neuroblastoma cells require much higher InsP 3 increases to induce Ca 2+ signaling than other cell types [ 37 ]. In search of an explanation for this unique feature, Watras et al has identified a protein in neurons that binds the InsP 3 receptor to significantly decrease its InsP 3 sensitivity [ 37 ]. This could make neuroblastoma cells (and perhaps other neuronal cell lines) less sensitive to InsP 3 increases requiring them to generate a lot more InsP 3 in response to agonists that could significantly displace the PLCδ1PH-GFP from the PM.…”

Section: Discussionmentioning

confidence: 99%

Live cell imaging with protein domains capable of recognizing phosphatidylinositol 4,5-bisphosphate; a comparative study

et al. 2009

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Background: Phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P 2 ] is a critically important regulatory phospholipid found in the plasma membrane of all eukaryotic cells. In addition to being a precursor of important second messengers, PtdIns(4,5)P 2 also regulates ion channels and transporters and serves the endocytic machinery by recruiting clathrin adaptor proteins. Visualization of the localization and dynamic changes in PtdIns(4,5)P 2 levels in living cells is critical to understanding the biology of PtdIns(4,5)P 2 . This has been mostly achieved with the use of the pleckstrin homology (PH) domain of PLC1 fused to GFP. Here we report on a comparative analysis of several recently-described yeast PH domains as well as the mammalian Tubby domain to evaluate their usefulness as PtdIns(4,5)P 2 imaging tools.

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“…Namely, the receptor density is significantly higher (13)(14)(15)(16) and the sensitivity to IP 3 is extraordinarily lower in vivo (17,18). It has been shown that the sensitivity of the Purkinje cell IP 3 R is similar to those of other cells when analyzed in isolation, leading to the hypothesis that the reduced sensitivity is due to interference by an inhibiting protein found in Purkinje cells (19,20). The physiological significance of these properties in terms of Ca 21 release before the onset of LTD is unclear at this time.…”

Section: Introductionmentioning

confidence: 99%

Modeling and Analysis of Calcium Signaling Events Leading to Long-Term Depression in Cerebellar Purkinje Cells

Hernjak¹,

Slepchenko²,

Fernald

et al. 2005

Biophysical Journal

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Modeling and simulation of the calcium signaling events that precede long-term depression of synaptic activity in cerebellar Purkinje cells are performed using the Virtual Cell biological modeling framework. It is found that the unusually high density and low sensitivity of inositol-1,4,5-trisphosphate receptors (IP3R) are critical to the ability of the cell to generate and localize a calcium spike in a single dendritic spine. The results also demonstrate the model's capability to simulate the supralinear calcium spike observed experimentally during coincident activation of the parallel and climbing fibers. The sensitivity of the calcium spikes to certain biological and geometrical effects is investigated as well as the mechanisms that underlie the cell's ability to generate the supralinear spike. The sensitivity of calcium release rates from the IP3R to calcium concentrations, as well as IP3 concentrations, allows the calcium spike to form. The diffusion barrier caused by the small radius of the spine neck is shown to be important, as a threshold radius is observed above which a spike cannot be formed. Additionally, the calcium buffer capacity and diffusion rates from the spine are found to be important parameters in shaping the calcium spike.

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Endogenous inhibitors of InsP3-induced Ca2+ release in neuroblastoma cells

Cited by 4 publications

References 43 publications

Where does all the PIP₂ come from?

Where does all the PIP₂ come from?

Live cell imaging with protein domains capable of recognizing phosphatidylinositol 4,5-bisphosphate; a comparative study

Modeling and Analysis of Calcium Signaling Events Leading to Long-Term Depression in Cerebellar Purkinje Cells

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Endogenous inhibitors of InsP3-induced Ca2+ release in neuroblastoma cells

Cited by 4 publications

References 43 publications

Where does all the PIP2 come from?

Where does all the PIP2 come from?

Live cell imaging with protein domains capable of recognizing phosphatidylinositol 4,5-bisphosphate; a comparative study

Modeling and Analysis of Calcium Signaling Events Leading to Long-Term Depression in Cerebellar Purkinje Cells

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Where does all the PIP₂ come from?

Where does all the PIP₂ come from?