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Biophys. J. BioFAST: First Published February 24, 2006. doi:10.1529/biophysj.105.072249
© 2006 by the Biophysical Society.

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BIOPHYSICAL THEORY AND MODELING

Model of IP3 and Ca2+ oscillations: Frequency encoding and identification of underlying feedbacks

Antonio Politi 1, Lawrence D Gaspers 2, Andrew P Thomas 2 and Thomas Höfer 1*

1 Humboldt University Berlin
2 University of Medicine and Dentistry of New Jersey

* To whom correspondence should be addressed. E-mail: thomas.hoefer{at}rz.hu-berlin.de.

Submitted on August 29, 2005
Revised on October 7, 2005
Accepted on 26 January 2006


  Abstract
Hormones that act through the calcium-releasing messenger, inositol 1,4,5-trisphosphate (IP3), cause intracellular calcium oscillations, which have been ascribed to calcium feedbacks on the IP3 receptor. Recent studies have shown that IP3 levels oscillate together with the cytoplasmic calcium concentration. To investigate the functional significance of this phenomenon, we have developed mathematical models of the interaction of both second messengers. The models account for both positive and negative feedbacks of calcium on IP3 metabolism, mediated by calcium activation of phospholipase C and IP3 3-kinase, respectively. The coupled IP3 and calcium oscillations have a greatly expanded frequency range compared to calcium fluctuations obtained with clamped IP3. Therefore the feedbacks can be physiologically important in supporting the efficient frequency encoding of hormone concentration observed in many cell types. This action of the feedbacks depends on the turnover rate of IP3. To shape the oscillations, positive feedback requires fast IP3 turnover, whereas negative feedback requires slow IP3 turnover. The ectopic expression of an IP3 binding protein has been used to decrease the rate of IP3 turnover experimentally, resulting in a dose-dependent slowing and eventual quenching of the Ca2+ oscillations. These results are consistent with a model based on positive feedback of Ca2+ on IP3 production.

Key Words: IP3 buffer, IP3 metabolism, bifurcation analysis, calcium signaling, feedback regulation, mathematical modeling




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Copyright © 2006 by the Biophysical Society.