CAREER: The Dynamics of IP3-Sensitive Calcium Release Sites

College Of William And Mary, Williamsburg VA

Investigators

Abstract

This faculty early career development award supports integrated research and educational activities in the interdisciplinary area of computational cell biology at the College of William and Mary. Professor Smith is developing a computational model of the dynamics of Ca2+ regulation at IP3-sensitive Ca2+ release sites that includes both 1) stochastic activation and inactivation of IP3Rs consistent with current knowledge of IP3 diversity and 2) a realistic account of the buffered diffusion of intracellular Ca2+ leading to cooperative IP3R activity. This model will be used to test four specific hypotheses. First, an optimal density of type 1 IP3Rs leads to maximum release site activation (but not so for type 2 IP3Rs). Second, Ca2+ buffers influence release site activation in a manner dependent on density and subtype of IP3Rs. Third, release sites exhibit distinct kinetics of activation and inactivation depending on IP3R subtype. Fourth, the dynamics of Ca2+ regulation at release sites with tightly clustered IP3Rs are well-approximated by reduced models utilizing steady-state Ca2+ microdomain theory. In addition, Prof. Smith is directing several interdisciplinary graduate/undergraduate research projects related to the statistical properties of IP3-sensitive Ca2+ release sites and the effect of IP3R clustering on global Ca2+ responses. Educational activities include curriculum development intended to increase the exposure of graduate and undergraduate students at William and Mary to quantitative approaches in cell and molecular biology. A new course entitled "Cellular Biophysics and Modeling" emphasizes diffusion, membrane transport, mass action kinetics, single channel recording of voltage- and ligand-gated ion channels, whole cell currents, compartmental modeling, plasma membrane electrical excitability, and dynamics in cell signal transduction. A second new course, "Introductory Bioinformatics," exposes biology majors (with minimal background in computer programming) to the basic algorithms of computational molecular biology including sequence comparison, fragment assembly, phylogenetic tree construction, and secondary structure prediction. Both courses include an integrated computer laboratory. This faculty early career development award supports computational cell biology research and education at the College of William and Mary. In most cell types an organelle called the endoplasmic reticulum (ER) has integrative and regenerative properties analogous to the excitable membranes of neurons. While insight into ER "Ca2+ excitability" has been obtained through the development of whole cell models of Ca2+ handling that are based on molecular mechanisms, a limitation of whole cell models to date is the assumption that IP3 receptors (IP3Rs) are globally coupled by the bulk (or average) cytosolic Ca2+ concentration. In order to overcome these limitations, Prof. Smith is developing computational models of the dynamics of Ca2+ regulation at IP3-sensitive Ca2+ release sites that focus on local coupling of IP3Rs mediated by the diffusion of intracellular Ca2+, a fundamental and significant aspect of cell signaling. Prof. Smith is also directing several interdisciplinary graduate/undergraduate research projects related to the statistical properties of IP3-sensitive Ca2+ release sites and the effect of IP3R clustering on global Ca2+ responses. Educational activities include curriculum development intended to increase the exposure of graduate and undergraduate students at William and Mary to quantitative approaches in cell and molecular biology. Two new courses are being developed: "Cellular Biophysics and Modeling" and "Introductory Bioinformatics," both of which involve an integrated computer laboratory.