Benjamin Engelhardt, Janine Holze, Christina Elliott, George S Baillie, Maik Kschischo, Holger Fröhlich
{"title":"CHO细胞中M$_{2}$受体依赖性联合信号和次级信使网络的建模和数学分析。","authors":"Benjamin Engelhardt, Janine Holze, Christina Elliott, George S Baillie, Maik Kschischo, Holger Fröhlich","doi":"10.1093/imammb/dqx003","DOIUrl":null,"url":null,"abstract":"<p><p>The muscarinic M$_{2}$ receptor is a prominent member of the GPCR family and strongly involved in heart diseases. Recently published experimental work explored the cellular response to iperoxo-induced M$_{2}$ receptor stimulation in Chinese hamster ovary (CHO) cells. To better understand these responses, we modelled and analysed the muscarinic M$_{2}$ receptor-dependent signalling pathway combined with relevant secondary messenger molecules using mass action. In our literature-based joint signalling and secondary messenger model, all binding and phosphorylation events are explicitly taken into account in order to enable subsequent stoichiometric matrix analysis. We propose constraint flux sampling (CFS) as a method to characterize the expected shift of the steady state reaction flux distribution due to the known amount of cAMP production and PDE4 activation. CFS correctly predicts an experimentally observable influence on the cytoskeleton structure (marked by actin and tubulin) and in consequence a change of the optical density of cells. In a second step, we use CFS to simulate the effect of knock-out experiments within our biological system, and thus to rank the influence of individual molecules on the observed change of the optical cell density. In particular, we confirm the relevance of the protein RGS14, which is supported by current literature. A combination of CFS with Elementary Flux Mode analysis enabled us to determine the possible underlying mechanism. Our analysis suggests that mathematical tools developed for metabolic network analysis can also be applied to mixed secondary messenger and signalling models. This could be very helpful to perform model checking with little effort and to generate hypotheses for further research if parameters are not known.</p>","PeriodicalId":49863,"journal":{"name":"Mathematical Medicine and Biology-A Journal of the Ima","volume":"35 3","pages":"279-297"},"PeriodicalIF":0.8000,"publicationDate":"2018-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/imammb/dqx003","citationCount":"0","resultStr":"{\"title\":\"Modelling and mathematical analysis of the M$_{2}$ receptor-dependent joint signalling and secondary messenger network in CHO cells.\",\"authors\":\"Benjamin Engelhardt, Janine Holze, Christina Elliott, George S Baillie, Maik Kschischo, Holger Fröhlich\",\"doi\":\"10.1093/imammb/dqx003\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The muscarinic M$_{2}$ receptor is a prominent member of the GPCR family and strongly involved in heart diseases. Recently published experimental work explored the cellular response to iperoxo-induced M$_{2}$ receptor stimulation in Chinese hamster ovary (CHO) cells. To better understand these responses, we modelled and analysed the muscarinic M$_{2}$ receptor-dependent signalling pathway combined with relevant secondary messenger molecules using mass action. In our literature-based joint signalling and secondary messenger model, all binding and phosphorylation events are explicitly taken into account in order to enable subsequent stoichiometric matrix analysis. We propose constraint flux sampling (CFS) as a method to characterize the expected shift of the steady state reaction flux distribution due to the known amount of cAMP production and PDE4 activation. CFS correctly predicts an experimentally observable influence on the cytoskeleton structure (marked by actin and tubulin) and in consequence a change of the optical density of cells. In a second step, we use CFS to simulate the effect of knock-out experiments within our biological system, and thus to rank the influence of individual molecules on the observed change of the optical cell density. In particular, we confirm the relevance of the protein RGS14, which is supported by current literature. A combination of CFS with Elementary Flux Mode analysis enabled us to determine the possible underlying mechanism. Our analysis suggests that mathematical tools developed for metabolic network analysis can also be applied to mixed secondary messenger and signalling models. This could be very helpful to perform model checking with little effort and to generate hypotheses for further research if parameters are not known.</p>\",\"PeriodicalId\":49863,\"journal\":{\"name\":\"Mathematical Medicine and Biology-A Journal of the Ima\",\"volume\":\"35 3\",\"pages\":\"279-297\"},\"PeriodicalIF\":0.8000,\"publicationDate\":\"2018-09-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1093/imammb/dqx003\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Mathematical Medicine and Biology-A Journal of the Ima\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1093/imammb/dqx003\",\"RegionNum\":4,\"RegionCategory\":\"数学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Mathematical Medicine and Biology-A Journal of the Ima","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1093/imammb/dqx003","RegionNum":4,"RegionCategory":"数学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOLOGY","Score":null,"Total":0}
Modelling and mathematical analysis of the M$_{2}$ receptor-dependent joint signalling and secondary messenger network in CHO cells.
The muscarinic M$_{2}$ receptor is a prominent member of the GPCR family and strongly involved in heart diseases. Recently published experimental work explored the cellular response to iperoxo-induced M$_{2}$ receptor stimulation in Chinese hamster ovary (CHO) cells. To better understand these responses, we modelled and analysed the muscarinic M$_{2}$ receptor-dependent signalling pathway combined with relevant secondary messenger molecules using mass action. In our literature-based joint signalling and secondary messenger model, all binding and phosphorylation events are explicitly taken into account in order to enable subsequent stoichiometric matrix analysis. We propose constraint flux sampling (CFS) as a method to characterize the expected shift of the steady state reaction flux distribution due to the known amount of cAMP production and PDE4 activation. CFS correctly predicts an experimentally observable influence on the cytoskeleton structure (marked by actin and tubulin) and in consequence a change of the optical density of cells. In a second step, we use CFS to simulate the effect of knock-out experiments within our biological system, and thus to rank the influence of individual molecules on the observed change of the optical cell density. In particular, we confirm the relevance of the protein RGS14, which is supported by current literature. A combination of CFS with Elementary Flux Mode analysis enabled us to determine the possible underlying mechanism. Our analysis suggests that mathematical tools developed for metabolic network analysis can also be applied to mixed secondary messenger and signalling models. This could be very helpful to perform model checking with little effort and to generate hypotheses for further research if parameters are not known.
期刊介绍:
Formerly the IMA Journal of Mathematics Applied in Medicine and Biology.
Mathematical Medicine and Biology publishes original articles with a significant mathematical content addressing topics in medicine and biology. Papers exploiting modern developments in applied mathematics are particularly welcome. The biomedical relevance of mathematical models should be demonstrated clearly and validation by comparison against experiment is strongly encouraged.
The journal welcomes contributions relevant to any area of the life sciences including:
-biomechanics-
biophysics-
cell biology-
developmental biology-
ecology and the environment-
epidemiology-
immunology-
infectious diseases-
neuroscience-
pharmacology-
physiology-
population biology