Biology subjects

Ohadi, D.

Publications and source records attributed to Ohadi, D..

4 recordsLinked to original sources

bioRxiv2020

Deciphering the postsynaptic calcium-mediated energy homeostasis through mitochondria-endoplasmic reticulum contact sites using systems modeling

Spatiotemporal compartmentation of calcium dynamics is critical for neuronal function, particularly in post-synaptic spines. This exquisite level of Ca2+ compartmentalization is achieved through the storage and release of Ca2+ from various intracellular organelles particularly the endoplasmic reticulum (ER) and the mitochondria. Mitochondria and ER are established storage organelles controlling Ca2+ dynamics in neurons. Mitochondria also generate a majority of energy used within postsynaptic spines to support the downstream events associated with neuronal stimulus. Recently, high resolution microscopy has unveiled direct contact sites between the ER and the mitochondria, which directly channel Ca2+ release from the ER into the mitochondrial membrane. In this study, we develop a computational 3D reaction-diffusion model to investigate the role of MERCs in regulating Ca2+ and ATP dynamics. This spatiotemporal model accounts for Ca2+ oscillations initiated by glutamate stimulus of metabotropic and ionotropic glutamate receptors and Ca2+ changes in four different compartments: cytosol, ER, mitochondria, and the MERC microdomain. Our simulations predict that the organization of these organelles and differential distribution of key Ca2+ channels such as IP3 receptor and ryanodine receptor modulate Ca2+ dynamics in response to different stimuli. We further show that the crosstalk between geometry (mitochondria and MERC) and metabolic parameters (cytosolic ATP hydrolysis, ATP generation) influences the cellular energy state. Our findings shed light on the importance of organelle interactions in predicting Ca2+ dynamics in synaptic signaling. Overall, our model predicts that a combination of MERC linkage and mitochondria size is necessary for optimal ATP production in the cytosol.

systems biology↗

bioRxiv2020

Spatially compartmentalized phase regulation of a Ca2+-cAMP-PKA oscillatory circuit

Signaling networks are spatiotemporally organized in order to sense diverse inputs, process information, and carry out specific cellular tasks. In pancreatic {beta} cells, Ca2+, cyclic adenosine monophosphate (cAMP), and Protein Kinase A (PKA) exist in an oscillatory circuit characterized by a high degree of feedback, which allows for specific signaling controls based on the oscillation frequencies. Here, we describe a novel mode of regulation within this circuit involving a spatial dependence of the relative phase between cAMP, PKA, and Ca2+. We show that nanodomain clustering of Ca2+-sensitive adenylyl cyclases drives oscillations of local cAMP levels to be precisely in-phase with Ca2+ oscillations, whereas Ca2+-sensitive phosphodiesterases maintain out-of-phase oscillations outside of the nanodomain, representing a striking example and novel mechanism of cAMP compartmentation. Disruption of this precise in-phase relationship perturbs Ca2+ oscillations, suggesting that the relative phase within an oscillatory circuit can encode specific functional information. This example of a signaling nanodomain utilized for localized tuning of an oscillatory circuit has broad implications for the spatiotemporal regulation of signaling networks.

cell biology↗

bioRxiv2019

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

Dendritic spines are the primary excitatory postsynaptic sites that act as subcompartments of signaling. Ca2+ is often the first and most rapid signal in spines. Downstream of calcium, the cAMP/PKA pathway plays a critical role in the regulation of spine formation, morphological modifications, and ultimately, learning and memory. While the dynamics of calcium are reasonably well-studied, calcium-induced cAMP/PKA dynamics, particularly with respect to frequency modulation, are not fully explored. In this study, we present a well-mixed model for the dynamics of calcium-induced cAMP/PKA dynamics in dendritic spines. The model is constrained using experimental observations in the literature. Further, we measured the calcium oscillation frequency in dendritic spines of cultured hippocampal CA1 neurons and used these dynamics as model inputs. Our model predicts that the various steps in this pathway act as frequency modulators for calcium and the high frequency of calcium input is filtered by AC1 and PDEs in this pathway such that cAMP/PKA only responds to lower frequencies. This prediction has important implications for noise filtering and long-timescale signal transduction in dendritic spines. A companion manuscript presents a three-dimensional spatial model for the same pathway.\n\nStatement of SignificancecAMP/PKA activity triggered by calcium is an essential biochemical pathway for synaptic plasticity, regulating spine structure, and long-term potentiation. In the current study, we predicted that for a given calcium input, AC1, and PDE1 kinetics reflect both the high and the low frequencies with different amplitudes and cAMP/PKA acts as a leaky integrator of calcium because of frequency attenuation by the intermediary steps. These findings have implications for cAMP/PKA signaling in dendritic spines in particular and neuronal signal transduction in general.

biophysics↗

bioRxiv2019

Geometric control of frequency modulation of cAMP oscillations due to Ca2+-bursts in dendritic spines

The spatiotemporal regulation of 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 the present work, we model the spatio-temporal dynamics of calcium-induced cAMP signaling pathway in dendritic spines. Using a 3D 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-to-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.

biophysics↗