Mathematical modelling of GPCR-mediated calcium signalling
Ca2+ is an important messenger which mediates several physiological functions, including muscle contraction, fertilisation, heart regulation and gene transcription. One major way its cytosolic level is raised is via a G-protein coupled receptor (GPCR)- mediated release from intracellular stores. GPC...
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| Format: | Thesis (University of Nottingham only) |
| Language: | English |
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2012
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| Online Access: | https://eprints.nottingham.ac.uk/12451/ |
| _version_ | 1848791503603761152 |
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| author | Majin, Wodu |
| author_facet | Majin, Wodu |
| author_sort | Majin, Wodu |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Ca2+ is an important messenger which mediates several physiological functions, including muscle contraction, fertilisation, heart regulation and gene transcription. One major way its cytosolic level is raised is via a G-protein coupled receptor (GPCR)- mediated release from intracellular stores. GPCR’s are the target of approximately 50% of all drugs in clinical use. Hence, understanding the underlying mechanisms of signalling in this pathway could lead to improved therapy in disease conditions associated with abnornmal Ca2+ signalling, and to the identification of new drug targets. To gain such insight, this thesis builds and analyses a detailed mathematical model of key processes leading to Ca2+ mobilisation.
Ca2+ signalling is considered in the particular context of the M3 muscarinic receptor system. Guided by available data, the Ca2+ mobilisation model is assembled, first by analysing a base G-protein activation model, and subsequently extending it with downstream details. Computationally efficient designs of a global parameter sensitivity analysis method are used to identify the key controlling parameters with respect to the main features of the Ca2+ data. The underlying mechanism behind the experimentally observed, rapid, amplified Ca2+ response is shown to be a rapid rate of inositol trisphosphate (IP3) formation from Phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. Using the same results, potential drug targets (apart fromthe GPCR) are identified, including the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and PIP2. Moreover, possible explanations for therapeutic failures were found when some parameters exerted a biphasic effect on the relative Ca2+ increase.
The sensitivity analysis results are used to simplify the process of parameter estimation by a significant reduction of the parameter space of interest. An evolutionary algorithm is used to successfully fit the model to a significant portion of the Ca2+ data. Subsequent sensitivity analyses of the best-fitting parameter sets suggest that mechanistic modelling of kinase-mediated GPCR desensitisation, and SERCA dynamics may be required for a comprehensive representation of the data. |
| first_indexed | 2025-11-14T18:29:33Z |
| format | Thesis (University of Nottingham only) |
| id | nottingham-12451 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T18:29:33Z |
| publishDate | 2012 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-124512025-02-28T11:19:23Z https://eprints.nottingham.ac.uk/12451/ Mathematical modelling of GPCR-mediated calcium signalling Majin, Wodu Ca2+ is an important messenger which mediates several physiological functions, including muscle contraction, fertilisation, heart regulation and gene transcription. One major way its cytosolic level is raised is via a G-protein coupled receptor (GPCR)- mediated release from intracellular stores. GPCR’s are the target of approximately 50% of all drugs in clinical use. Hence, understanding the underlying mechanisms of signalling in this pathway could lead to improved therapy in disease conditions associated with abnornmal Ca2+ signalling, and to the identification of new drug targets. To gain such insight, this thesis builds and analyses a detailed mathematical model of key processes leading to Ca2+ mobilisation. Ca2+ signalling is considered in the particular context of the M3 muscarinic receptor system. Guided by available data, the Ca2+ mobilisation model is assembled, first by analysing a base G-protein activation model, and subsequently extending it with downstream details. Computationally efficient designs of a global parameter sensitivity analysis method are used to identify the key controlling parameters with respect to the main features of the Ca2+ data. The underlying mechanism behind the experimentally observed, rapid, amplified Ca2+ response is shown to be a rapid rate of inositol trisphosphate (IP3) formation from Phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. Using the same results, potential drug targets (apart fromthe GPCR) are identified, including the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and PIP2. Moreover, possible explanations for therapeutic failures were found when some parameters exerted a biphasic effect on the relative Ca2+ increase. The sensitivity analysis results are used to simplify the process of parameter estimation by a significant reduction of the parameter space of interest. An evolutionary algorithm is used to successfully fit the model to a significant portion of the Ca2+ data. Subsequent sensitivity analyses of the best-fitting parameter sets suggest that mechanistic modelling of kinase-mediated GPCR desensitisation, and SERCA dynamics may be required for a comprehensive representation of the data. 2012-07-19 Thesis (University of Nottingham only) NonPeerReviewed application/pdf en arr https://eprints.nottingham.ac.uk/12451/1/general.pdf Majin, Wodu (2012) Mathematical modelling of GPCR-mediated calcium signalling. PhD thesis, University of Nottingham. |
| spellingShingle | Majin, Wodu Mathematical modelling of GPCR-mediated calcium signalling |
| title | Mathematical modelling of GPCR-mediated calcium signalling |
| title_full | Mathematical modelling of GPCR-mediated calcium signalling |
| title_fullStr | Mathematical modelling of GPCR-mediated calcium signalling |
| title_full_unstemmed | Mathematical modelling of GPCR-mediated calcium signalling |
| title_short | Mathematical modelling of GPCR-mediated calcium signalling |
| title_sort | mathematical modelling of gpcr-mediated calcium signalling |
| url | https://eprints.nottingham.ac.uk/12451/ |