MS04 - CDEV-2
Suzanne M. Scharer Room (#3146) in The Ohio Union

Stochastic effects in cell biology across scales

Tuesday, July 18 at 04:00pm

SMB2023 SMB2023 Follow Tuesday during the "MS04" time block.
Room assignment: Suzanne M. Scharer Room (#3146) in The Ohio Union.
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James MacLaurin, Victor Matveev


Experimental evidence strongly suggests that stochasticity is widespread at the cellular level. There is a great need to understand how microscopic noise affects physiologically relevant cellular processes across scales, from the stochastic behavior of channels and receptors, to the stochastic dynamical phenomena guiding populations of cells such as tumors. The goal of this minisymposium is to bring together researchers exploring the role of stochasticity at diverse scales, with the goal of promoting the exchange of approaches and mathematical tools used to model and understand stochastic effects at different levels. For example, Gregory Conradi D. Smith (College of William & Mary) will present his work on how the stochastic allosteric binding of receptor dimers determines the activation properties of G-protein coupled receptors. Further, Martin Falcke (Max Delbrück Center, Berlin) will preset his latest research on how microscopic stochastic gating of single IP3 receptor-coupled channel organizes to produce collective channel opening events underlying cell-wide phenomena such as waves of calcium concentration. In his talk, Victor Matveev (NJIT) will compare the efficiency of modeling methods used to simulate stochastic neurotransmitter and hormone vesicle fusion, which is guided by stochastic calcium ion diffusion, buffering and binding. Finally, addressing the role of stochasticity at larger scales, Linh Huynh (University of Utah) will describe the role of stochastic effects in the tumor microenvironment on cancer cell dynamics.

Martin Falcke

Max Delbrück Center for Molecular Medicine (Mathematical Cell Physiology)
"Modeling IP3-induced Ca2+ signaling based on its interspike interval statistics"
Inositol 1,4,5-trisphosphate (IP3) induced Ca2+ signaling is used by almost all eukaryotic cells. Recent research demonstrated its randomness on all structural levels and large cell variability of the average interspike interval (ISI). Nonetheless, we compile eight general properties of Ca2+ spiking common to all cell types and pathways investigated hitherto. Stimulation response relation and moment relation of ISI exhibit specific robustness properties. We suggest an analytic theory of Ca2+ spiking calculating the moments of the ISI distribution. It captures all general properties, their robustness properties, cell variability and pathway specific behavior. We explain cell variability by variability of channel cluster coupling by Ca2+-induced Ca2+ release and the number of clusters. We predict the relation between puff probability and agonist concentration, and [IP3] and agonist concentration. Pathway and cell type specific behaviour is explained by the different types of negative feedback terminating spikes. In summary, the hierarchical random character of spike generation explains all of the general properties.

Greg Conradi Smith

William & Mary (Applied Science / Neuroscience / CAMS Biomath)
"Allosteric coupling and cycle kinetics of G protein-coupled receptor dimers"
Quantitative pharmacologists construct Markov chain models to give insight into the relationship between ligand concentration and the fraction of cell surface receptors in each of several molecular conformations. Pharmacologists use these stochastic models to understand the action of natural ligands and drugs on receptor-mediated cell responses. When receptors function as two or more similar protein subunits working in concert (i.e., homodimers or oligomers), receptor models must (i) account for symmetry, (ii) satisfy thermodynamic constraints, and (iii) properly account for subunit interactions (allostery) mediated by conformational coupling. The modeling framework that satisfies these three requirements will be explicated in the context of models of G protein-coupled receptors (GPCRs), such as metabotropic glutamate receptors, that function as multi-molecule signaling complexes. For equilibrium models of receptor dimers, this approach facilitates the inference of a parsimonious subset of allosteric interactions leading to conformational coupling and dependence of receptor subunits. I will also discuss progress on extending this framework to the analysis of non-equilibrium steady-state cycle kinetics of GPCRs (e.g., nucleotide exchange).
Additional authors: Spenser E. Wood; Lindsay Stolting

Victor Matveev

New Jersey Institute of Technology (Department of Mathematical Sciences)
"Accuracy of deterministic vs. stochastic modeling of Ca2+-triggered vesicle fusion latency"
High degree of variability is a characteristic feature of synaptic neurotransmitter release, which is important to consider in our understanding and modeling of this fundamental physiological process. Although stochastic Ca2+ channel gating is one of the primary source of this variability, it can be implemented in a computationally inexpensive way in combination with deterministic simulation of the downstream Ca2+ diffusion and binding. Another fundamental reason for the high variability of synaptic response is that only a small number of Ca2+ ions enter the synaptic terminal through a single channel during an action potential. This fact entails large fluctuations due to Ca2+ diffusion and its binding to Ca2+ buffers and vesicle release sensors, leading to a widely-held view that solving continuous deterministic reaction-diffusion equations does not provide high accuracy when modeling Ca2+-dependent cell processes. However, several comparative studies show a surprising close agreement between deterministic and trial-averaged stochastic simulations of Ca2+ dynamics, as long as Ca2+ channel gating is not Ca2+-dependent. This result deserves careful investigation. In this talk I will present further analysis and comparison of stochastic and mass-action modeling of vesicle release, showing that the discrepancy between deterministic and stochastic approaches remains small even when only as few as 40-50 ions enter per single channel-vesicle complex. The reason for the close agreement between stochastic and mass-action simulations is that the discrepancy between the two approaches is determined by the size of the correlation between the local Ca2+ concentration and the state of the vesicle release sensor, rather than fluctuation amplitude. Whereas diffusion and buffering increases fluctuation size, the same processes appear to de-correlate fluctuations in Ca2+ concentration from fluctuations in Ca2+ sensor binding state. Finally, contrary to naïve intuition, the mass action / mean-field reaction-diffusion description allows an accurate estimate of the entire probability distribution of vesicle release latency (first-passage time), rather than providing information about trial-averaged quantities only. These results may help in the choice of appropriate and efficient tools for the modeling of this and other fundamental biochemical cell processes.

Linh Huynh

University of Utah (Mathematics)
"Stochastic Cancer Cell Dynamics under Environmental Stress"
One reason cancer remains very difficult to eradicate is its remarkable adaptability to the environment. In this talk, I will discuss how stochasticity and collective behavior help cancer cells survive and adapt under environmental stress in two different contexts: (1) when ecological interactions between cells in a heterogeneous population facilitate cancer’s stochastic escape from drug treatments and (2) when inflammation in the tumor microenvironment facilitates stochastic tumor growth.

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