Computational modeling reveals frequency modulation of calcium-cAMP/PKA pathway in dendritic spines

Ohadi, Donya; Schmitt, Danielle L.; Calabrese, Barbara; Halpain, Shelley; Zhang, Jin; Rangamani, Padmini

doi:10.1101/521740

Cited by 21 publications

(30 citation statements)

References 134 publications

(108 reference statements)

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“…Our results show that spatial localization of enzymes on the spine membrane and in the cytoplasm can alter the temporal response of cAMP to induced calcium transients. Thus, in addition to kinetic properties as shown previously (15), we predict that the spatial organization of molecules in the dendritic spine can affect how cAMP/PKA dynamics respond to calcium input.…”

Section: Introductionmentioning

confidence: 53%

“…It is also well known that calcium spikes are necessary for changes in cAMP concentrations, but only certain bursts of calcium spikes increase cAMP levels in neurons (11). The dynamics of calcium-induced cAMP has been modeled by us and others (15,27,48,74) with a focus on identifying the mechanisms underlying interdependent oscillations. We showed that cAMP is primarily sensitive to the longer timescale effects of calcium rather than the shorter timescales (15).…”

Section: Discussionmentioning

confidence: 99%

“…Calcium dynamics are modeled as sinusoidal oscillations with exponential decays based on the experimental observations on the second and minute timescales. The second-scale oscillations (0.5 Hz) were set up based on experimental observations in our companion study (15), and minute-scale oscillations (0.003 Hz) were inspired by Gorbunova and Spitzer's (11) observations.…”

Section: Timescalesmentioning

confidence: 99%

“…In response to calcium influx, cAMP transients have been reported in neurons (11), and cAMP/ PKA dynamics are tightly coupled to that of calcium (12)(13)(14). In a companion study, we developed a computational model for calcium-induced cAMP/PKA activity in neurons (15) and predicted that the cAMP/PKA pathway acts as a leaky integrator of calcium signals. We also experimentally showed that calcium spontaneously oscillates in dendritic spines of hippocampal subregional volumes, Cornu Ammonis 1 (CA1) neurons (15).…”

Section: Introductionmentioning

confidence: 99%

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Geometric Control of Frequency Modulation of cAMP Oscillations due to Calcium in Dendritic Spines

Ohadi

Rangamani

2019

Biophysical Journal

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The spatiotemporal regulation of cyclic adenosine monophosphate (cAMP) and its dynamic interactions with other second messengers such as calcium are critical features of signaling specificity required for neuronal development and connectivity. cAMP is known to contribute to long-term potentiation and memory formation by controlling the formation and regulation of dendritic spines. Despite the recent advances in biosensing techniques for monitoring spatiotemporal cAMP dynamics, the underlying molecular mechanisms that attribute to the subcellular modulation of cAMP remain unknown. In this work, we model the spatiotemporal dynamics of calcium-induced cAMP signaling pathway in dendritic spines. Using a three-dimensional reaction-diffusion model, we investigate the effect of different spatial characteristics of cAMP dynamics that may be responsible for subcellular regulation of cAMP concentrations. Our model predicts that the volume/surface ratio of the spine, regulated through the spine head size, spine neck size, and the presence of physical barriers (spine apparatus), is an important regulator of cAMP dynamics. Furthermore, localization of the enzymes responsible for the synthesis and degradation of cAMP in different compartments also modulates the oscillatory patterns of cAMP through exponential relationships. Our findings shed light on the significance of complex geometric and localization relationships for cAMP dynamics in dendritic spines.

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Section: Introductionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Timescalesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Geometric Control of Frequency Modulation of cAMP Oscillations due to Calcium in Dendritic Spines

Ohadi

Rangamani

2019

Biophysical Journal

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“…For example, fluorescence experiments have shown that the dendritic spine necks act as a diffusion barrier to calcium ions, preventing ions from entering the dendritic shaft [59]. Complementary to this and other experiments, various physical models solving reaction-diffusion equations in idealized geometries have been developed to further interrogate the structure-function relationships [41,53,[64][65][66][67].…”

Section: Discussionmentioning

confidence: 99%

GAMer 2: A System for 3D Mesh Processing of Cellular Electron Micrographs

Lee

Laughlin

Beaumelle

et al. 2019

Preprint

Self Cite

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Recent advances in electron microscopy have, for the first time, enabled imaging of single cells in 3D at a nanometer length scale resolution. An uncharted frontier for in silico biology is the ability to simulate cellular processes using these observed geometries. Enabling such simulations will require a system for going from electron micrographs to 3D volume meshes, which can then form the basis of computer simulations of such processes using numerical techniques such as the Finite Element Method (FEM). In this paper, we develop an end-to-end pipeline for this task by adapting and extending computer graphics mesh processing and smoothing algorithms. Our workflow makes use of our recently rewritten mesh processing software, GAMer 2, which implements several mesh conditioning algorithms and serves as a platform to connect different pipeline steps. We apply this pipeline to a series of electron micrographs of neuronal dendrite morphology explored at three different length scales and demonstrate that the resultant meshes are suitable for finite element simulations. Our pipeline, which consists of free and open-source community driven tools, is a step towards routine physical simulations of biological processes in realistic geometries. We posit that a new frontier at the intersection of computational technologies and single cell biology is now open. Innovations in algorithms to reconstruct and simulate cellular length scale phenomena based on emerging structural data will enable realistic physical models and advance discovery. Author summary3D imaging of cellular components and associated reconstruction methods have made great strides in the past decade, opening windows into the complex intraceullar organization. These advances also mean that computational tools need to be developed to work with these images not just for purposes of visualization but also for biophysical simulations. Here, we describe a pipeline that takes images from electron microscopy as input and produces smooth surface and volume meshes as output. These meshes are suitable for building high-quality finite element simulations of cellular processes modeled by ordinary and partial differential equations, bringing us closer to realizing the goal of generating high-resolution simulations of such phenomena in realistic geometries. We demonstrate the utility of this pipeline by meshing 3D reconstructions of dendritic spines, calculating 1 the curvatures of the different component membranes, and conducting finite-element simulations of reaction-diffusion equations using the generated meshes. The software tools employed in our pipeline are community driven, open source, and free. We believe that technologies such as those presented will enable a new frontier in biophysical simulations in realistic geometries.

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Cleaved PINK1 induces neuronal plasticity through PKA‐mediated BDNF functional regulation

Soman

Tingle

Dagda

et al. 2021

J of Neuroscience Research

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Mutations in PTEN‐induced kinase 1 (PINK1) lead to early onset autosomal recessive Parkinson's disease in humans. In healthy neurons, full‐length PINK1 (fPINK1) is post‐translationally cleaved into different lower molecular weight forms, and cleaved PINK1 (cPINK1) gets shuttled to the cytosolic compartments to support extra‐mitochondrial functions. While numerous studies have exemplified the role of mitochondrially localized PINK1 in modulating mitophagy in oxidatively stressed neurons, little is known regarding the physiological role of cPINK1 in healthy neurons. We have previously shown that cPINK1, but not fPINK1, modulates the neurite outgrowth and the maintenance of dendritic arbors by activating downstream protein kinase A (PKA) signaling in healthy neurons. However, the molecular mechanisms by which cPINK1 promotes neurite outgrowth remain to be elucidated. In this report, we show that cPINK1 supports neuronal development by modulating the expression and extracellular release of brain‐derived neurotrophic factor (BDNF). Consistent with this role, we observed a progressive increase in the level of endogenous cPINK1 but not fPINK1 during prenatal and postnatal development of mouse brains and during development in primary cortical neurons. In cultured primary neurons, the pharmacological activation of endogenous PINK1 leads to enhanced downstream PKA activity, subsequent activation of the PKA‐modulated transcription factor cAMP response element‐binding protein (CREB), increased intracellular production and extracellular release of BDNF, and enhanced activation of the BDNF receptor‐TRKβ. Mechanistically, cPINK1‐mediated increased dendrite complexity requires the binding of extracellular BDNF to TRKβ. In summary, our data support a physiological role of cPINK1 in stimulating neuronal development by activating the PKA‐CREB‐BDNF signaling axis in a feedforward loop.

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Computational modeling reveals frequency modulation of calcium-cAMP/PKA pathway in dendritic spines

Cited by 21 publications

References 134 publications

Geometric Control of Frequency Modulation of cAMP Oscillations due to Calcium in Dendritic Spines

Geometric Control of Frequency Modulation of cAMP Oscillations due to Calcium in Dendritic Spines

GAMer 2: A System for 3D Mesh Processing of Cellular Electron Micrographs

Cleaved PINK1 induces neuronal plasticity through PKA‐mediated BDNF functional regulation

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