Models of IP sub(3) and Ca super(2+) Oscillations: Frequency Encoding and Identification of Underlying Feedbacks

• Published in: Biophysical journal 2006-05, Vol.90 (9), p.3120-3133
• Main Authors: Politi, A, Gaspers, L D, Thomas, AP, Hoefer, T
• Format: Article
• Language: English
• ISSN: 0006-3495
• DOI: 10.1529/biophysj.105.072249

Hormones that act through the calcium-releasing messenger, inositol 1,4,5-trisphosphate (IP sub(3)), cause intracellular calcium oscillations, which have been ascribed to calcium feedbacks on the IP sub(3) receptor. Recent studies have shown that IP sub(3) 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 IP sub(3) metabolism, mediated by calcium activation of phospholipase C and IP sub(3) 3-kinase, respectively. The coupled IP sub(3) and calcium oscillations have a greatly expanded frequency range compared to calcium fluctuations obtained with clamped IP sub(3). 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 IP sub(3). To shape the oscillations, positive feedback requires fast IP sub(3) turnover, whereas negative feedback requires slow IP sub(3) turnover. The ectopic expression of an IP sub(3) binding protein has been used to decrease the rate of IP sub(3) turnover experimentally, resulting in a dose-dependent slowing and eventual quenching of the Ca super(2+) oscillations. These results are consistent with a model based on positive feedback of Ca super(2+) on IP sub(3) production.