Exploring the rate-limiting steps in visual phototransduction recovery by bottom-up kinetic modeling

Cell Communication and Signaling

Research

Daniele Dell’Orco¹  Karl-Wilhelm Koch²  Ludovica Montanucci³  Brandon M Invergo³  Jaume Bertranpetit³ 

[1] Department of Life Sciences and Reproduction, Section of Biological Chemistry and Center for BioMedical Computing (CBMC), University of Verona, Strada le Grazie 8, 37134, Verona, Italy;Department of Neurosciences, Biochemistry Group, University of Oldenburg, Oldenburg, Germany;IBE – Institute of Evolutionary Biology (CSIC-Universitat Pompeu Fabra), CEXS-UPF-PRBB, Barcelona, Catalonia, Spain;

关键词: Visual phototransduction;    G-protein-coupled receptor signaling;    Arrestin;    Recoverin;    Kinetic modeling;    Systems biology;   

DOI  :  10.1186/1478-811X-11-36

 received in 2013-02-21, accepted in 2013-05-09,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundPhototransduction in vertebrate photoreceptor cells represents a paradigm of signaling pathways mediated by G-protein-coupled receptors (GPCRs), which share common modules linking the initiation of the cascade to the final response of the cell. In this work, we focused on the recovery phase of the visual photoresponse, which is comprised of several interacting mechanisms.ResultsWe employed current biochemical knowledge to investigate the response mechanisms of a comprehensive model of the visual phototransduction pathway. In particular, we have improved the model by implementing a more detailed representation of the recoverin (Rec)-mediated calcium feedback on rhodopsin kinase and including a dynamic arrestin (Arr) oligomerization mechanism. The model was successfully employed to investigate the rate limiting steps in the recovery of the rod photoreceptor cell after illumination. Simulation of experimental conditions in which the expression levels of rhodospin kinase (RK), of the regulator of the G-protein signaling (RGS), of Arr and of Rec were altered individually or in combination revealed severe kinetic constraints to the dynamics of the overall network.ConclusionsOur simulations confirm that RGS-mediated effector shutdown is the rate-limiting step in the recovery of the photoreceptor and show that the dynamic formation and dissociation of Arr homodimers and homotetramers at different light intensities significantly affect the timing of rhodopsin shutdown. The transition of Arr from its oligomeric storage forms to its monomeric form serves to temper its availability in the functional state. Our results may explain the puzzling evidence that overexpressing RK does not influence the saturation time of rod cells at bright light stimuli. The approach presented here could be extended to the study of other GPCR signaling pathways.

【 授权许可】

Unknown   
© Invergo et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.