Inositol 1,4,-trisphosphate (InsP3) is a ubiquitous second messenger generated through the hydrolysis of phosphatidyl inositol 4,5 bisphosphate by phospholipase C. InsP3 binds to a family of very similar receptor proteins localized to the endoplasmic reticulum and mediates the release of intrcellular calcium through an intrinsic calcium channel. Intracellular calcium release via the InsP3 has been implicated in a multitude of cell biological processes ranging from mesoderm induction in the developing Xenopus to increased contractile force in cardiac muscle. Three highly similar isoforms of the receptor family have been cloned and sequenced. Mutagenesis studied have enabled the assignment of a three domain model for the receptors functional organization consisting of a NH2-terminal ligand binding doman, a C-terminal calcium channel domain and a central coupling or regulatory domain. The receptor assembles into functional tetramers through several distinct yet additive determinants that are located within the channel domain. These assembly determinants include the receptor 5th and 6th membrane spanning sequences, as well as a region of the carboxyl terminus. This region of the receptor encodes the intrinsic calcium channel and shares significant homology with the ryanodine receptor channel.
The specific aims of this proposals are to test: 1) The hypothesis that membrane spanning regions 5,6 and the C-terminus are key determinants of InsP3R oligomerization: 2) The hypothesis that elements within membrane spanning regions 1-4 are key to the transduction of ligand binding to channel gating: 3) The hypothesis that membrane spanning regions 5,6 and the intervening luminal loop contain sequence elements critical for channel permeation properties: 4) Define the 3D shape of native and recombinant InsP3R channels by cryoelectron microscopy and angular reconstruction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH053367-06
Application #
6196681
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (03))
Program Officer
Asanuma, Chiiko
Project Start
1995-07-01
Project End
2005-06-30
Budget Start
2000-07-22
Budget End
2001-06-30
Support Year
6
Fiscal Year
2000
Total Cost
$293,038
Indirect Cost
Name
Loyola University Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Maddux, Jean-Marie; Holland, Peter C (2011) Effects of dorsal or ventral medial prefrontal cortical lesions on five-choice serial reaction time performance in rats. Behav Brain Res 221:63-74
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Ramos, Jorge; Jung, Wonyong; Ramos-Franco, Josefina et al. (2003) Single channel function of inositol 1,4,5-trisphosphate receptor type-1 and -2 isoform domain-swap chimeras. J Gen Physiol 121:399-411