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Microfluidic interrogation and mathematical modeling of multi-regime calcium signaling dynamics.

ABSTRACT: Through microfluidic interrogation we analyzed real-time calcium responses of HEK293 cells stimulated with short pulses of the M3 muscarinic receptor ligand carbachol in two different concentration regimes. Lower ligand concentrations elicit oscillatory calcium signals while higher concentrations trigger a rapid rise that eventually settles down at a steady-state slightly above pre-stimulus levels, referred to as an acute signal. Cells were periodically pulsed with carbachol at these two concentration regimes using a custom-made microfluidic platform, and the resulting calcium signals were measured with a single fluorescent readout. Pulsed stimulations at these two concentration regimes resulted in multiple types of response patterns that each delivered complementary information about the M3 muscarinic receptor signaling pathway. These multiple types of calcium response patterns enabled development of a comprehensive mathematical model of multi-regime calcium signaling. The resulting model suggests that dephosphorylation of deactivated receptors is rate limiting for recovery of calcium signals in the acute regime (high ligand concentration), while calcium replenishment and IP3 production determine signal recovery in the oscillatory regime (low ligand concentration). This study not only provides mechanistic insight into multi-regime signaling of the M3 muscarinic receptor pathway, but also provides a general strategy for analyzing multi-regime pathways using only one fluorescent readout.

SUBMITTER: Jovic A

PROVIDER: S-EPMC3704220 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Microfluidic interrogation and mathematical modeling of multi-regime calcium signaling dynamics.

Jovic Andreja A Wade Susan M SM Neubig Richard R RR Linderman Jennifer J JJ Takayama Shuichi S

Integrative biology : quantitative biosciences from nano to macro 20130604 7

Through microfluidic interrogation we analyzed real-time calcium responses of HEK293 cells stimulated with short pulses of the M3 muscarinic receptor ligand carbachol in two different concentration regimes. Lower ligand concentrations elicit oscillatory calcium signals while higher concentrations trigger a rapid rise that eventually settles down at a steady-state slightly above pre-stimulus levels, referred to as an acute signal. Cells were periodically pulsed with carbachol at these two concent ...[more]

PMID: 23732791

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Project description:In synapses, calcium is required for modulating synaptic transmission, plasticity, synaptogenesis, and synaptic pruning. The regulation of calcium dynamics within neurons involves cellular mechanisms such as synaptically activated channels and pumps, calcium buffers, and calcium sequestrating organelles. Many experimental studies tend to focus on only one or a small number of these mechanisms, as technical limitations make it difficult to observe all features at once. Computational modeling enables incorporation of many of these properties together, allowing for more complete and integrated studies. However, the scale of existing detailed models is often limited to synaptic and dendritic compartments as the computational burden rapidly increases when these models are integrated in cellular or network level simulations. In this article we present a computational model of calcium dynamics at the postsynaptic spine of a CA1 pyramidal neuron, as well as a methodology that enables its implementation in multi-scale, large-scale simulations. We first present a mechanistic model that includes individually validated models of various components involved in the regulation of calcium at the spine. We validated our mechanistic model by comparing simulated calcium levels to experimental data found in the literature. We performed additional simulations with the mechanistic model to determine how the simulated calcium activity varies with respect to presynaptic-postsynaptic stimulation intervals and spine distance from the soma. We then developed an input-output (IO) model that complements the mechanistic calcium model and provide a computationally efficient representation for use in larger scale modeling studies; we show the performance of the IO model compared to the mechanistic model in terms of accuracy and speed. The models presented here help achieve two objectives. First, the mechanistic model provides a comprehensive platform to describe spine calcium dynamics based on individual contributing factors. Second, the IO model is trained on the main dynamical features of the mechanistic model and enables nonlinear spine calcium modeling on the cell and network level simulation scales. Utilizing both model representations provide a multi-level perspective on calcium dynamics, originating from the molecular interactions at spines and propagating the effects to higher levels of activity involved in network behavior.

Project description:ObjectiveThe objective of this study is to conduct a systematic review of multi-scale HIV immunoepidemiological models to improve our understanding of the synergistic impact between the HIV viral-immune dynamics at the individual level and HIV transmission dynamics at the population level.BackgroundWhile within-host and between-host models of HIV dynamics have been well studied at a single scale, connecting the immunological and epidemiological scales through multi-scale models is an emerging method to infer the synergistic dynamics of HIV at the individual and population levels.MethodsWe reviewed nine articles using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) framework that focused on the synergistic dynamics of HIV immunoepidemiological models at the individual and population levels.ResultsHIV immunoepidemiological models simulate viral immune dynamics at the within-host scale and the epidemiological transmission dynamics at the between-host scale. They account for longitudinal changes in the immune viral dynamics of HIV+ individuals, and their corresponding impact on the transmission dynamics in the population. They are useful to analyze the dynamics of HIV super-infection, co-infection, drug resistance, evolution, and treatment in HIV+ individuals, and their impact on the epidemic pathways in the population. We illustrate the coupling mechanisms of the within-host and between-host scales, their mathematical implementation, and the clinical and public health problems that are appropriate for analysis using HIV immunoepidemiological models.ConclusionHIV immunoepidemiological models connect the within-host immune dynamics at the individual level and the epidemiological transmission dynamics at the population level. While multi-scale models add complexity over a single-scale model, they account for the time varying immune viral response of HIV+ individuals, and the corresponding impact on the time-varying risk of transmission of HIV+ individuals to other susceptibles in the population.

Dataset Information

Microfluidic interrogation and mathematical modeling of multi-regime calcium signaling dynamics.

Publications

Microfluidic interrogation and mathematical modeling of multi-regime calcium signaling dynamics.

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