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¹ Richard D. Berlin Center for Cell Analysis and Modelling, University of Connecticut Health Center, Farmington, CT 06030, USA

Despite its very low concentration in the plasma membrane, PIP₂ is the precursor for the important second messenger InsP₃ and, independently, is a key modulator of membrane signalling molecules such as ion channels. However, it has been difficult to determine the spatial and temporal characteristics of PIP₂ and InsP₃ during a cell signalling event. Our laboratory used bradykinin stimulation of N1E-115 neuroblastoma cells to infer the InsP₃ dynamics from calcium imaging studies, biochemical analysis and InsP₃ uncaging. We have used computational modelling with Virtual Cell to help analyse and interpret experimental data on the details of the calcium release process as well as to build a comprehensive image-based model of agonist-induced calcium release in a neuronal cell. These data provided a constraint for the further investigation of how low levels of cellular PIP₂ could provide sufficient InsP₃ for calcium release. Using biochemical assays, quantitative imaging of GFP-based probe translocation and computational analysis, it was shown that PIP₂ synthesis is stimulated concomitant with its hydrolysis. This mechanism should be important not just for consideration of PIP₂ as a precursor of InsP₃, but for any pathway that can be directly or indirectly modulated by PIP₂.

(Received 20 March 2007; accepted after revision 28 March 2007; first published online 29 March 2007)
Corresponding author L. M. Loew: Richard D. Berlin Center for Cell Analysis and Modelling, University of Connecticut Health Center, Farmington, CT 06030, USA. Email: les{at}volt.uchc.edu

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