An extracellular stimulus evokes a specific response from its target cell - for example, it may command the release or uptake of nutrient, promote neurotransmitter release, or initiate muscle contraction. The information inherent in the stimulus is frequently translated into a format that can then be conveyed by intracellular emissaries: the intracellular levels and hence the activities of these "second messengers" are regulated according to the strength and duration of the original stimulus. This process - signal transduction - is fundamental to how an organism responds and adapts to changes in the environment. Unfortunately, there are many ways it can be disrupted in disease states and by environmental toxins. The adequate treatment of such disturbances requires us to have an understanding of the precise molecular mechanisms that are involved. We study the physiological actions of the inositol polyphosphate second messengers, particularly metabolites of InsP5 and InsP6. We have discovered that InsP5 is metabolically poised to respond to an appropriate cell stimulus by being metabolized to a novel second messenger - an InsP4 - that regulates Ca2+-dependent Cl- channels in the plasma membrane. These ion channels participate in salt and fluid secretion, smooth muscle contraction, neurotransmission, bone remodeling, tumor cell migration, osmoregulation and volume-dependent metabolic effects. With regards to InsP6, we have shown it is a precursor for other important derivatives: the "pyrophosphorylated" polyphosphates. We are exploring the significance of these novel metabolites, and the information uncovered to date strongly suggests they are "high-energy" molecules that act as sensors of specific environmental stress stimulii and nutrient deprivation. Recent data also suggest roles in tissue repair.

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