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Computational modelling elucidates the mechanism of ciliary regulation in health and disease

BACKGROUND: Ciliary dysfunction leads to a number of human pathologies, including primary ciliary dyskinesia, nephronophthisis, situs inversus pathology or infertility. The mechanism of cilia beating regulation is complex and despite extensive experimental characterization remains poorly understood....

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Autores principales: Kotov, Nikolay V, Bates, Declan G, Gizatullina, Antonina N, Gilaziev, Bulat, Khairullin, Rustem N, Chen, Michael ZQ, Drozdov, Ignat, Umezawa, Yoshinori, Hundhausen, Christian, Aleksandrov, Alexey, Yan, Xing-gang, Spurgeon, Sarah K, Smales, C Mark, Valeyev, Najl V
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3224258/
https://www.ncbi.nlm.nih.gov/pubmed/21920041
http://dx.doi.org/10.1186/1752-0509-5-143
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author Kotov, Nikolay V
Bates, Declan G
Gizatullina, Antonina N
Gilaziev, Bulat
Khairullin, Rustem N
Chen, Michael ZQ
Drozdov, Ignat
Umezawa, Yoshinori
Hundhausen, Christian
Aleksandrov, Alexey
Yan, Xing-gang
Spurgeon, Sarah K
Smales, C Mark
Valeyev, Najl V
author_facet Kotov, Nikolay V
Bates, Declan G
Gizatullina, Antonina N
Gilaziev, Bulat
Khairullin, Rustem N
Chen, Michael ZQ
Drozdov, Ignat
Umezawa, Yoshinori
Hundhausen, Christian
Aleksandrov, Alexey
Yan, Xing-gang
Spurgeon, Sarah K
Smales, C Mark
Valeyev, Najl V
author_sort Kotov, Nikolay V
collection PubMed
description BACKGROUND: Ciliary dysfunction leads to a number of human pathologies, including primary ciliary dyskinesia, nephronophthisis, situs inversus pathology or infertility. The mechanism of cilia beating regulation is complex and despite extensive experimental characterization remains poorly understood. We develop a detailed systems model for calcium, membrane potential and cyclic nucleotide-dependent ciliary motility regulation. RESULTS: The model describes the intimate relationship between calcium and potassium ionic concentrations inside and outside of cilia with membrane voltage and, for the first time, describes a novel type of ciliary excitability which plays the major role in ciliary movement regulation. Our model describes a mechanism that allows ciliary excitation to be robust over a wide physiological range of extracellular ionic concentrations. The model predicts the existence of several dynamic modes of ciliary regulation, such as the generation of intraciliary Ca(2+ )spike with amplitude proportional to the degree of membrane depolarization, the ability to maintain stable oscillations, monostable multivibrator regimes, all of which are initiated by variability in ionic concentrations that translate into altered membrane voltage. CONCLUSIONS: Computational investigation of the model offers several new insights into the underlying molecular mechanisms of ciliary pathologies. According to our analysis, the reported dynamic regulatory modes can be a physiological reaction to alterations in the extracellular environment. However, modification of the dynamic modes, as a result of genetic mutations or environmental conditions, can cause a life threatening pathology.
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spelling pubmed-32242582011-11-30 Computational modelling elucidates the mechanism of ciliary regulation in health and disease Kotov, Nikolay V Bates, Declan G Gizatullina, Antonina N Gilaziev, Bulat Khairullin, Rustem N Chen, Michael ZQ Drozdov, Ignat Umezawa, Yoshinori Hundhausen, Christian Aleksandrov, Alexey Yan, Xing-gang Spurgeon, Sarah K Smales, C Mark Valeyev, Najl V BMC Syst Biol Research Article BACKGROUND: Ciliary dysfunction leads to a number of human pathologies, including primary ciliary dyskinesia, nephronophthisis, situs inversus pathology or infertility. The mechanism of cilia beating regulation is complex and despite extensive experimental characterization remains poorly understood. We develop a detailed systems model for calcium, membrane potential and cyclic nucleotide-dependent ciliary motility regulation. RESULTS: The model describes the intimate relationship between calcium and potassium ionic concentrations inside and outside of cilia with membrane voltage and, for the first time, describes a novel type of ciliary excitability which plays the major role in ciliary movement regulation. Our model describes a mechanism that allows ciliary excitation to be robust over a wide physiological range of extracellular ionic concentrations. The model predicts the existence of several dynamic modes of ciliary regulation, such as the generation of intraciliary Ca(2+ )spike with amplitude proportional to the degree of membrane depolarization, the ability to maintain stable oscillations, monostable multivibrator regimes, all of which are initiated by variability in ionic concentrations that translate into altered membrane voltage. CONCLUSIONS: Computational investigation of the model offers several new insights into the underlying molecular mechanisms of ciliary pathologies. According to our analysis, the reported dynamic regulatory modes can be a physiological reaction to alterations in the extracellular environment. However, modification of the dynamic modes, as a result of genetic mutations or environmental conditions, can cause a life threatening pathology. BioMed Central 2011-09-15 /pmc/articles/PMC3224258/ /pubmed/21920041 http://dx.doi.org/10.1186/1752-0509-5-143 Text en Copyright ©2011 Kotov et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 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.
spellingShingle Research Article
Kotov, Nikolay V
Bates, Declan G
Gizatullina, Antonina N
Gilaziev, Bulat
Khairullin, Rustem N
Chen, Michael ZQ
Drozdov, Ignat
Umezawa, Yoshinori
Hundhausen, Christian
Aleksandrov, Alexey
Yan, Xing-gang
Spurgeon, Sarah K
Smales, C Mark
Valeyev, Najl V
Computational modelling elucidates the mechanism of ciliary regulation in health and disease
title Computational modelling elucidates the mechanism of ciliary regulation in health and disease
title_full Computational modelling elucidates the mechanism of ciliary regulation in health and disease
title_fullStr Computational modelling elucidates the mechanism of ciliary regulation in health and disease
title_full_unstemmed Computational modelling elucidates the mechanism of ciliary regulation in health and disease
title_short Computational modelling elucidates the mechanism of ciliary regulation in health and disease
title_sort computational modelling elucidates the mechanism of ciliary regulation in health and disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3224258/
https://www.ncbi.nlm.nih.gov/pubmed/21920041
http://dx.doi.org/10.1186/1752-0509-5-143
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