Modelling calcium-dependent proteins in the spine - challenges and solutions

Abstract

Event Abstract Back to Event Modelling calcium-dependent proteins in the spine - challenges and solutions Melanie I. Stefan1*, Shirley Pepke1, Stefan Mihalas1, Thomas Bartol2, Terrence Sejnowki2 and Mary B. Kennedy1 1 California Institute of Technology, Biology Division, United States 2 Salk Institute, United States Synaptic plasticity is mediated by calcium signalling in the postsynaptic spine. One hypothesis suggests that the direction of plasticity is determined by the relative activation of two Ca2+-/calmodulin dependent proteins, CaMKII and calcineurin [Lisman. PNAS, 1989], and the subsequent activation of tightly regulated signalling pathways in the spine. Computational modelling allows us to gain an insight into how proteins within this complex signalling pathway may be regulated and in turn regulate each other. It can also improve understanding of its complex and often non-intuitive behaviour under varying conditions. Three features of this signalling system pose a challenge to computational modellers: First, the absolute number of molecules in a dendritic spine is small, which makes reactions stochastic and affects competition between proteins. Second, the constrained geometry within the dendritic spine affects diffusion and creates distinct, dynamic signalling microdomains. Third, the large number of possible modifications on signalling proteins such as CaMKII increases combinatorial complexity and requires modelling strategies that can work with large numbers of possible states. To manage all three of these challenges, we are using the spatial stochastic simulator MCell [Kerr et al. SIAM J Sci Comput, 2008]. MCell is an agent-based Monte-Carlo simulator that allows stochastic modelling in arbitrarily complex geometries. It is therefore ideally suited to model systems with small molecule numbers and spatial constraints. A realistic reconstruction of a portion of a dendrite has recently been used for modelling calcium transients within CA1 neurons using MCell [Keller et al. submitted]. We are currently combining this technology with an earlier kinetic model of calmodulin activation by calcium [Pepke et al. PLoS Comput Biol, 2010] to explore the relationship between calcium signalling, calmodulin activation and the regulation of calmodulin targets in the spine. As an agent-based simulator, MCell allows for simulation of multistate signalling systems which are so complex as to be intractable using ODE/PDE or the Gillespie algorithm. This allows us to use MCell to construct a detailed model of CaMKII activation that includes all the complexities of calmodulin binding [Stefan et al. PLoS ONE, 2012], phosphorylation [Miller and Kennedy. Cell, 1986], conformational change and intramolecular regulation [Chao et al. Nat Struct Mol Biol, 2010]. Keywords: computational neuroscience, modelling, Calcium signalling, calcium dependent proteins, computational modeling Conference: 5th INCF Congress of Neuroinformatics, Munich, Germany, 10 Sep - 12 Sep, 2012. Presentation Type: Poster Topic: Neuroinformatics Citation: Stefan M, Pepke S, Mihalas S, Bartol T, Sejnowki T and Kennedy M (2014). Modelling calcium-dependent proteins in the spine - challenges and solutions. Front. Neuroinform. Conference Abstract: 5th INCF Congress of Neuroinformatics. doi: 10.3389/conf.fninf.2014.08.00091 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 21 Mar 2013; Published Online: 27 Feb 2014. * Correspondence: Dr. Melanie I. Stefan, California Institute of Technology, Biology Division, Pasadena, United States, mstefan@caltech.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Melanie I. Stefan Shirley Pepke Stefan Mihalas Thomas Bartol Terrence Sejnowki Mary B. Kennedy Google Melanie I. Stefan Shirley Pepke Stefan Mihalas Thomas Bartol Terrence Sejnowki Mary B. Kennedy Google Scholar Melanie I. Stefan Shirley Pepke Stefan Mihalas Thomas Bartol Terrence Sejnowki Mary B. Kennedy PubMed Melanie I. Stefan Shirley Pepke Stefan Mihalas Thomas Bartol Terrence Sejnowki Mary B. Kennedy Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.