Propogating waves of Ca2+ have been observed by physiologists in a wide variety of cellular systems, ranging from secretory cells in the pancreas to neurons. These waves appear to function as part of the second messenger role of Ca2+ in transmitting signals from hormone receptors and other molecular detectors in the plasma membrane. In mature oocytes Ca2+ waves are initiated by the egg-sperm fusion event and have been observed in every species studied. In the mature Xenopus laevis oocyte, as in mammalian species, the inositol phospholipid cascade has been demonstrated to be the major signal transduction pathway involved in these waves. The proposed research investigates the mechanism of initiation, propogation, and termination of the fertilization wave in the mature Xenopus laevis oocyte by developing computer-based models of the primary Ca2+ handling mechanisms in this cell. Development and analysis of these kinetic mechanisms will be modular, i.e., individual steps in the overall mechanism will be fine-tuned to experimental measurements before being combined into a 3-dimensional model. The 3-dimensional model, necessitated by the large size of the oocyte (1.2mm), will include diffusion of Ca2+ in the presence of exogenous and endogenous buffers, diffusion of inositol 1,4,5-trisphosphate (IP3), and Ca2+ handling by the endoplasmic reticulum, mitochondria, and plasma membrane. To insure that model parameters are chosen correctly and to test predictions of the model, experiments that establish the rate of Ca2+ handling will be performed in the stratified mature Xenopus laevis oocyte, a novel preparation that permits separation of cellular organelles in vivo. Simulations will be carried out to help test hypotheses regarding possible mechanisms of initiation, propogation and termination of the fertilization wave. Additional calculations will be performed to help interpret on-going experiments with the unstratified egg. Because IP3-induced Ca2+ release from the endoplasmic reticulum is the major process involved in the fertilization wave in mammalian eggs, the African frog, Xenopus laevis, is a good biological model for fertilization in mammals. After dormancy for many years, fertilization stimulates events that activate the metabolism and development of an egg cell. This research will help clarify the role that the Ca2+ wave plays in these important physiological processes.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Research Project (R01)
Project #
5R01RR010081-03
Application #
2685816
Study Section
Special Emphasis Panel (ZRG2-PHY (01))
Project Start
1996-03-01
Project End
2001-03-02
Budget Start
1998-03-03
Budget End
1999-03-02
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California Davis
Department
Miscellaneous
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Wagner, John; Fall, Christopher P; Hong, Feng et al. (2004) A wave of IP3 production accompanies the fertilization Ca2+ wave in the egg of the frog, Xenopus laevis: theoretical and experimental support. Cell Calcium 35:433-47
Fall, Christopher P; Wagner, John M; Loew, Leslie M et al. (2004) Cortically restricted production of IP3 leads to propagation of the fertilization Ca2+ wave along the cell surface in a model of the Xenopus egg. J Theor Biol 231:487-96
Bugrim, Andrej; Fontanilla, Ray; Eutenier, Bridget B et al. (2003) Sperm initiate a Ca2+ wave in frog eggs that is more similar to Ca2+ waves initiated by IP3 than by Ca2+. Biophys J 84:1580-90
Bugrim, A E (1999) Regulation of Ca2+ release by cAMP-dependent protein kinase. A mechanism for agonist-specific calcium signaling? Cell Calcium 25:219-26
Dawson, S P; Keizer, J; Pearson, J E (1999) Fire-diffuse-fire model of dynamics of intracellular calcium waves. Proc Natl Acad Sci U S A 96:6060-3
Csutora, P; Su, Z; Kim, H Y et al. (1999) Calcium influx factor is synthesized by yeast and mammalian cells depleted of organellar calcium stores. Proc Natl Acad Sci U S A 96:121-6
Magnus, G; Keizer, J (1998) Model of beta-cell mitochondrial calcium handling and electrical activity. I. Cytoplasmic variables. Am J Physiol 274:C1158-73
Keizer, J; Smith, G D (1998) Spark-to-wave transition: saltatory transmission of calcium waves in cardiac myocytes. Biophys Chem 72:87-100
Keizer, J; Smith, G D; Ponce-Dawson, S et al. (1998) Saltatory propagation of Ca2+ waves by Ca2+ sparks. Biophys J 75:595-600
Wagner, J; Li, Y X; Pearson, J et al. (1998) Simulation of the fertilization Ca2+ wave in Xenopus laevis eggs. Biophys J 75:2088-97

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