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A reverse chemical genetics and chemical biology approach to probing inositol 1,4,5-trisphosphate receptor function

Reference	BBS/E/B/0000L152
Principal Investigator / Supervisor	Dr Martin Bootman
Co-Investigators / Co-Supervisors
Institution	Babraham Institute
Department	Babraham Institute Department
Funding type	Research
Value (£)	2,760
Status	Completed
Type	Institute Project
Start date	01/04/2005
End date	31/03/2008
Duration	36 months

Abstract

Calcium (Ca2+) is an almost universal intracellular messenger, controlling a diverse range of cellular processes, such as gene transcription, muscle contraction and cell proliferation. In most cells Ca2+ has its major signalling function when its concentration is elevated in the cytosolic compartment. There are two ways in which intracellular Ca2+ ([Ca2+]i) concentration can be increased, either by influx of Ca2+ from the intracellular space through ion channels in the plasma membrane, or via release of Ca2+ from defined intracellular stores. These [Ca2+]i stores are released by activation of ligand gated ion channels, of which inositol 1,4,5-trisphosphate receptors (InsP3Rs) are a principal type. The X-ray crystal structure of the InsP3 binding domain of a particular type of InsP3R (mouse type 1) has recently been reported. This structure provides vital information about the InsP3Rs, and is indicative of what structural features are required for a InsP3 to interact with InsP3Rs. Although the crystal structure of the free form of the receptor was not reported, gel filtration experiments suggest that InsP3Rs undergo a large conformation change on InsP3 binding, which leads to channel opening, and this postulate is supported by electron microscopy analysis of InsP3R1. Although there are a number of compounds that selectively activate InsP3Rs, there are currently no potent, selective InsP3R antagonists available. The existing antagonists of InsP3 action include polyanionic compounds such as heparin, pentosan polysulphate and 2-aminoethoxydiphenylborate. These agents inhibit InsP3-mediated responses, but their specificity is so poor that they are not applicable in many situations. We intend to further characterise the site where InsP3Rs bind InsP3, and to develop experimentally useful antagonists of this interaction. These novel compounds will allow us to probe the contribution of InsP3Rs in cellular responses.

Summary

unavailable

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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