Cell Calcium 42 (2007) 556–564 Modeling Ca 2+ signaling differentiation during oocyte maturation Ghanim Ullah a , Peter Jung a,∗ , Khaled Machaca b,∗∗ a Department of Physics and Astronomy and Quantitative Biology Institute, Ohio University, Athens, OH 45701, USA b Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA Received 13 December 2006; received in revised form 19 January 2007; accepted 25 January 2007 Available online 8 March 2007 Abstract Ca 2+ is a fundamental intracellular signal that mediates a variety of disparate physiological functions often in the same cell. Ca 2+ signals span a wide range of spatial and temporal scales, which endow them with the specificity required to induce defined cellular functions. Furthermore, Ca 2+ signaling is highly plastic as it is modulated dynamically during normal physiological development and under pathological conditions. However, the molecular mechanisms underlying Ca 2+ signaling differentiation during cellular development remain poorly understood. Oocyte maturation in preparation for fertilization provides an exceptionally well-suited model to elucidate Ca 2+ signaling regulation during cellular development. This is because a Ca 2+ signal with specialized spatial and temporal dynamics is universally essential for egg activation at fertilization. Here we use mathematical modeling to define the critical determinants of Ca 2+ signaling differentiation during oocyte maturation. We show that increasing IP 3 receptor (IP 3 R) affinity replicates both elementary and global Ca 2+ dynamics observed experimentally following oocyte maturation. Furthermore, our model reveals that because of the Ca 2+ dependency of both SERCA and the IP 3 R, increased IP 3 R affinity shifts the system’s equilibrium to a new steady state of high cytosolic Ca 2+ , which is essential for fertilization. Therefore our model provides unique insights into how relatively small alterations of the basic molecular mechanisms of Ca 2+ signaling components can lead to dramatic alterations in the spatio-temporal properties of Ca 2+ dynamics. © 2007 Elsevier Ltd. All rights reserved. Keywords: Calcium signaling; Oocyte maturation; Mathematical modeling; Xenopus; IP3 receptor; Plasma membrane Ca-ATPase 1. Introduction Ca 2+ is a fundamental second messenger that mediates a plethora of cellular functions ranging from neurotrans- mitter release to fertilization. Specificity in Ca 2+ signaling is encoded in the spatial, temporal and amplitude features of cytoplasmic Ca 2+ (Ca cyt 2+ ) dynamics [1]. That is, in the same cell Ca 2+ signals of disparate duration, amplitude or ∗ Corresponding author at: Clippinger 252B, Athens, OH 45701, USA. Tel.: +1 740 593 1720; fax: +1 740 593 0433. ∗∗ Corresponding author at: 4301 West Markham St. Slot 505, Little Rock, AR 72205, USA. Tel.: +1 501 603 1596; fax: +1 501 686 8167. E-mail addresses: jung@helios.phy.ohiou.edu (P. Jung), kamachaca@uams.edu (K. Machaca). frequency result in different cellular responses. For exam- ple, localized Ca 2+ release through ryanodine receptors in vascular smooth muscle leads to vasodilation [2], whereas global sustained Ca 2+ signals lead to vasoconstriction [3]. Ca 2+ signals achieve this specificity by differentially acti- vating Ca 2+ -dependent effectors based on their frequency, location, duration and amplitude. Although, much is known about Ca 2+ signaling specificity, the mechanisms regulating developmental acquisition of this specificity are poorly defined. At different stages of cellu- lar differentiation, the cell’s competence to produce specific Ca 2+ dynamics varies. Therefore, Ca 2+ signals differenti- ate concomitantly with cellular development to serve the need of the cell throughout its growth and differentiation. Furthermore, Ca 2+ signaling components remodel during 0143-4160/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ceca.2007.01.010