Skip to main content
Log in

Multiple Timescales, Mixed Mode Oscillations and Canards in Models of Intracellular Calcium Dynamics

  • Published:
Journal of Nonlinear Science Aims and scope Submit manuscript

Abstract

A range of representative models of intracellular calcium dynamics are surveyed, with the aim of determining which model characteristics are qualitatively unchanged by changes to details of the model components. Techniques from geometric singular perturbation theory are used to investigate the role of separation of timescales in determining model dynamics, with particular emphasis on identifying parameter regimes in which mixed mode oscillations are present as a result of the separation of timescales. We find that the number of distinct timescales and the number of variables evolving on each timescale varies between models and depends on both the model assumptions and on the parameter regime of interest within the model, but in all cases, the presence of canards and associated mixed mode oscillations provides a mechanism by which the models can robustly exhibit complex oscillations, with the frequency of oscillation depending sensitively on parameter values. We find that analysis of the number and nature of the distinct timescales in a model allows us to make useful predictions about the dynamics associated with the model, and that this may give us more information about the model dynamics than a classification according to the modelling assumptions made about different cellular mechanisms in deriving the models.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Atri, A., Amundsen, J., Clapham, D., Sneyd, J.: A single-pool model for intracellular calcium oscillations and waves in the Xenopus laevis oocyte. Biophys. J. 65, 1727–1739 (1993)

    Article  Google Scholar 

  • Benoit, E., Callot, J.F., Diener, F., Diener, M.: Chasse au canard. Collect. Math. 31, 37–119 (1981)

    Google Scholar 

  • Brøns, M., Krupa, M., Wechselberger, M.: Mixed mode oscillations due to the generalized canard phenomenon. Fields Inst. Commun. 49, 39–63 (2006)

    Google Scholar 

  • De Young, G.W., Keizer, J.: A single pool IP3-receptor based model for agonist stimulated Ca2+ oscillations. Proc. Natl. Acad. Sci. USA 89, 9895–9899 (1992)

    Article  Google Scholar 

  • Desroches, M., Guckenheimer, J., Krauskopf, B., Kuehn, C., Osinga, H., Wechselberger, M.: Mixed-mode oscillatons with multiple time scales. SIAM Rev. (2011)

  • Doedel, E.J.: AUTO-07P: Continuation and bifurcation software for ordinary differential equations. http://indy.cs.concordia.ca/auto (2007)

  • Domijan, M., Murray, R., Sneyd, J.: Dynamical probing of the mechanisms underlying calcium oscillations. J. Nonlinear Sci. 16, 483–506 (2006)

    Article  MathSciNet  MATH  Google Scholar 

  • Dupont, G., Erneux, C.: Simulations of the effects of inositol 1,4,5-trisphosphate 3-kinase and 5-phosphatase activities on Ca2+ oscillations. Cell Calcium 22, 321–331 (1997)

    Article  Google Scholar 

  • Dupont, G., Swillens, S.: Quantal release, incremental detection, and long-period Ca2+ oscillations in a model based on regulatory Ca2+ binding sites along the permeation pathway. Biophys. J. 71, 1714–1722 (1996)

    Article  Google Scholar 

  • Ermentrout, B.: Simulating, Analyzing, and Animating Dynamical Systems: A Guide to XPPAUT for Researchers and Students. SIAM, Philadelphia (2002)

    Book  MATH  Google Scholar 

  • Falcke, M.: Reading the patterns in living cells—the physics of Ca2+ signaling. Adv. Phys. 53, 225–440 (2004)

    Article  Google Scholar 

  • Guckenheimer, J.: Singular Hopf bifurcation in systems with two slow variables. SIAM J. Appl. Dyn. Syst. 7, 1355–1377 (2008)

    Article  MathSciNet  MATH  Google Scholar 

  • Harvey, E., Kirk, V., Osinga, H., Sneyd, J., Wechselberger, M.: Understanding anomalous delays in a model of intracellular calcium dynamics. Chaos 20, 045104 (2010)

    Article  MathSciNet  Google Scholar 

  • Keener, J., Sneyd, J.: Mathematical Physiology, 2nd edn. Springer, New York (2008)

    Google Scholar 

  • Krupa, M., Szmolyan, P.: Relaxation oscillations and canard explosion. J. Differ. Equ. 174, 312–368 (2001)

    Article  MathSciNet  MATH  Google Scholar 

  • Krupa, M., Wechselberger, M.: Local analysis near a folded saddle-node singularity. J. Differ. Equ. 248, 2841–2888 (2010)

    Article  MathSciNet  MATH  Google Scholar 

  • Krupa, M., Popovic, N., Kopell, N.: Mixed-mode oscillations in three timescale systems: A prototypical example. SIAM J. Appl. Dyn. Syst. 7, 361–420 (2008)

    Article  MathSciNet  MATH  Google Scholar 

  • Li, Y.X., Rinzel, J.: Equations for InsP3 receptor-mediated [Ca2+] i oscillations derived from a detailed kinetic model: a Hodgkin–Huxley like formalism. J. Theor. Biol. 166, 461–473 (1994)

    Article  Google Scholar 

  • Politi, A., Gaspers, L.D., Thomas, A.P., Höfer, T.: Models of IP3 and Ca2+ oscillations: Frequency encoding and identification of underlying feedbacks. Biophys. J. 90, 3120–3133 (2006)

    Article  Google Scholar 

  • Rotstein, H.G., Wechselberger, M., Kopell, N.: Canard induced mixed-mode oscillations in a medial entorhinal cortex layer II stellate cell model. SIAM J. Appl. Dyn. Syst. 7, 1582–1611 (2008)

    Article  MathSciNet  MATH  Google Scholar 

  • Rubin, J., Wechselberger, M.: Giant squid—hidden canard: the 3D geometry of the Hodgkin Huxley model. Biol. Cybern. 97, 5–32 (2007)

    Article  MathSciNet  MATH  Google Scholar 

  • Sims, C.E., Allbritton, N.L.: Metabolism of inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate by the oocytes of Xenopus laevis. J. Biol. Chem. 273, 4052–4058 (1998)

    Article  Google Scholar 

  • Sneyd, J., Tsaneva-Atanasova, K., Yule, D.I., Thompson, J.L., Shuttleworth, T.J.: Control of calcium oscillations by membrane fluxes. Proc. Natl. Acad. Sci. USA 101, 1392–1396 (2004)

    Article  Google Scholar 

  • Sneyd, J., Tsaneva-Atanasova, K., Reznikov, V., Bai, Y., Sanderson, M.J., Yule, D.I.: A method for determining the dependence of calcium oscillations on inositol trisphosphate oscillations. Proc. Natl. Acad. Sci. USA 103, 1675–1680 (2006)

    Article  Google Scholar 

  • Swillens, S., Combettes, L., Champeil, P.: Transient inositol 1,4,5-trisphosphate-induced Ca2+ release: A model based on regulatory Ca2+-binding sites along the permeation pathway. Proc. Natl. Acad. Sci. USA 91, 10074–10078 (1994)

    Article  Google Scholar 

  • Szmolyan, P., Wechselberger, M.: Canards in ℝ3. J. Differ. Equ. 177, 419–453 (2001)

    Article  MathSciNet  MATH  Google Scholar 

  • Tang, Y., Stephenson, J.L., Othmer, H.G.: Simplification and analysis of models of calcium dynamics based on IP3-sensitive calcium channel kinetics. Biophys. J. 70, 246–263 (1996)

    Article  Google Scholar 

  • Wechselberger, M.: Existence and bifurcation of canards in ℝ3 in the case of a folded node. SIAM J. Appl. Dyn. Syst. 4, 101–139 (2005)

    Article  MathSciNet  MATH  Google Scholar 

  • Wechselberger, M.: A propos de canards (Apropos canards). Trans. Am. Math. Soc. (2011)

  • Wechselberger, M., Weckesser, W.: Bifurcations of mixed-mode oscillations in a stellate cell model. Physica D 238, 1598–1614 (2009)

    Article  MATH  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Emily Harvey.

Additional information

Communicated by P Newton.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harvey, E., Kirk, V., Wechselberger, M. et al. Multiple Timescales, Mixed Mode Oscillations and Canards in Models of Intracellular Calcium Dynamics. J Nonlinear Sci 21, 639–683 (2011). https://doi.org/10.1007/s00332-011-9096-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00332-011-9096-z

Keywords

Mathematics Subject Classification (2000)

Navigation