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, 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 perform a valuable function: they are """"""""high-energy"""""""" molecules whose turnover is regulated by specific environmental stress stimulii.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES080046-18
Application #
7328864
Study Section
(LST)
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2006
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Sung, Eui Jae; Shears, Stephen B (2018) A genome-wide dsRNA library screen for Drosophila genes that regulate the GBP/phospholipase C signaling axis that links inflammation to aging. BMC Res Notes 11:884
Wang, Li-Dong; Bi, Xiuli; Song, Xin et al. (2013) A sequence variant in the phospholipase C epsilon C2 domain is associated with esophageal carcinoma and esophagitis. Mol Carcinog 52 Suppl 1:E80-6
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