Activation of cell-surface receptors releases inside cells inositol (1,4,5) trisphosphate (I(1,4,5)P3), a ubiquitous signal playing a pivotal role in cell regulation through initiation of calcium fluxes. Enzymes that metabolize and thereby deactivate (I(1,4,5)P3) are crucial to the regulation of cell signalling. Moreover, increasing evidence points to the ensuing metabolites themselves having important roles in signal transduction. Particular attention is being focused on IP5 and IP6, since data from this laboratory, in collaboration with the Calcium Regulation Section of LCMP, has shown a novel consequence of receptor occupation to be a stimulation of IP5 breakdown to I(3,4,5,6)P4. This project aims to under- stand how metabolism of inositol phosphates is regulated by extracellular agents such as hormones, toxins (including carcinogens) and clinically important drugs; inositol phosphate fluxes in isolated cells and cell lines, and the influence of extracellular agents, will be monitored to seek possible control points. Complementary techniques are either in use or being developed: (a) isolation of enzymes from cell extracts in both unregulated and regulated states, (b) reconstitution of purified enzymes with Ca2+/calmodulin, A-kinase and C-kinase and (c) cloning,and expressing key enzymes in cell-lines to study physiological effects. Growing evidence (largely from this laboratory) also, points to feedforward and feedback regulation by inositol phosphates themselves. As the complexities of this system are unravelled, we will better understand and treat the effects of extracellular toxins on cell signalling.
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