Crosstalk between G-protein and Ca2+ pathways switches intracellularcAMP levels

Valeyev, Najl V.; Heslop-Harrison, J. S.; Postlethwaite, Ian; Gizatullina, Antonina N.; Kotov, Nikolay V.; Bates, Declan G.

doi:10.1039/b807993e

Cited by 9 publications

(14 citation statements)

References 65 publications

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“…One module combines all Ca 2+ and K + currents that define intraciliary Ca 2+ homeostasis and the transmembrane potential. One of the most essential intraciliary Ca 2+ binding proteins, CaM [63,64], selectively regulates the activities of adenylate cyclase (AC), guanylate cyclase (GC) and phosphodiesterases (PDE), and thereby modulates the intraciliary levels of adenosine monophosphate (cAMP) and guanosine monophosphate (cGMP) in a Ca 2+ dependent manner [65]. The cAMP- and cGMP-dependent kinases phosphorylate dynein proteins in the bases of cilia and thereby induce the mechanical cilia movement.…”

Section: Resultsmentioning

confidence: 99%

“…In a previous work we showed that the ciliary beat frequency can have a "double" bell shape dependence on Ca 2+ concentration [65] due to the differential regulation of adenylate and guanylate cyclase isoforms in a Ca 2+ -calmodulin (CaM) dependent manner [63,64]. One bell-shape was due to the cAMP production by a combination of AC and PDE, whereas another one was mediated by cGMP production and degradation.…”

Section: Resultsmentioning

confidence: 99%

“…Here we extend our previous analysis and describe the conditions when one or the other peak can be significantly reduced or even disappear. Figure 15A shows the model predictions for the ciliary beat frequency in comparison with the experimental data [65,80]. Recent studies demonstrated that hormones and pharmacological agents can regulate both function and structure of cilia by interfering with the cyclic nucleotide signalling pathways [81,82].…”

Section: Resultsmentioning

confidence: 99%

“…The result of the cross-talk between membrane potential and a variety of channels is that intraciliary Ca 2+ can shift between several dynamic modes. The steady-state and dynamic Ca 2+ alterations regulate the intraciliary levels of cAMP and cGMP in a Ca 2+ -CaM-dependent manner via the AC, GC and PDE isoforms [65]. Cyclic nucleotides, in turn, define the degree of phosphorylation of dynein filaments in the bases of ciliary axoneme via PKA and PKG kinases.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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BackgroundCiliary 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.ResultsThe 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 Ca2+ 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.ConclusionsComputational 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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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“…An in-depth analysis of the Ca 2+ and G-protein cross-talk mechanisms is presented in ref. 48. The Erk2 Fig.…”

Section: A New Model For Camp Oscillations In Dictyostelium Exhibits mentioning

confidence: 98%

Computational modelling suggests dynamic interactions between Ca2+, IP3 and G protein-coupled modules are key to robust Dictyostelium aggregation

et al. 2009

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Under conditions of starvation, Dictyostelium cells begin a programme of development during which they aggregate to form a multicellular structure by chemotaxis, guided by propagating waves of cyclic AMP that are relayed robustly from cell to cell. In this paper, we develop and analyse a new model for the intracellular and extracellular cAMP dependent processes that regulate Dictyostelium migration. The model allows, for the first time, a quantitative analysis of the dynamic interactions between calcium, IP 3 and G protein-dependent modules that are shown to be key to the generation of robust cAMP oscillations in Dictyostelium cells. The model provides a mechanistic explanation for the transient increase in cytosolic free Ca 2+ concentration seen in recent experiments with the application of the calmodulin inhibitor calmidazolium (R24571) to Dictyostelium cells, and also allows elucidation of the effects of varying both the conductivity of stretch-activated channels and the concentration of external phosphodiesterase on the oscillatory regime of an individual cell. A rigorous analysis of the robustness of the new model shows that interactions between the different modules significantly reduce the sensitivity of the resulting cAMP oscillations to variations in the kinetics of different Dictyostelium cells, an essential requirement for the generation of the spatially and temporally synchronised chemoattractant cAMP waves that guide Dictyostelium aggregation.

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Systems Biology of Cell Behavior

Valeyev

Bates

Umezawa

et al. 2010

Methods in Molecular Biology

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Systems Biology approaches to drug discovery largely focus on the increasing understanding of intracellular and cellular circuits, by computational representation of a molecular system followed by parameter validation against experimental data. This chapter outlines a universal approach to systems biology that allows the linking of intracellular molecular machinery and cellular activity. This procedure is achieved by applying mathematical modeling to molecular modules of a cell in the light of systems biology techniques.

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Crosstalk between G-protein and Ca2+ pathways switches intracellularcAMP levels

Cited by 9 publications

References 65 publications

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

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

Computational modelling suggests dynamic interactions between Ca2+, IP3 and G protein-coupled modules are key to robust Dictyostelium aggregation

Systems Biology of Cell Behavior

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